Means and methods for anti-vegf therapy

ABSTRACT

The present application relates to the field of cancer, particularly to colorectal cancer (CRC). A panel of biomarkers is presented herein that can be used to cluster CRC samples into distinct genetic subtypes. It further relates to the use of the clustering method on patients treated with an anti-VEGF therapy and the identification of anti-VEGF responsive genetic subtypes.

FIELD OF THE INVENTION

The present application relates to the field of cancer, particularly to colorectal cancer (CRC). A panel of biomarkers is presented herein that can be used to cluster CRC samples into distinct genetic subtypes. It further relates to the use of the clustering method on patients treated with an anti-VEGF therapy and the identification of anti-VEGF responsive genetic subtypes.

BACKGROUND

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women and an important contributor to cancer mortality and morbidity. CRC develops through an ordered series of events beginning with the transformation of normal colonic epithelium to an adenomatous intermediate and then ultimately adenocarcinoma, the so-called “adenoma-carcinoma sequence” (Pino and Chung, 2010). It is now generally accepted that multiple genetic events are required for tumor progression and that the temporal acquisition of these genetic changes matters. Recent genome-wide sequencing efforts have calculated as many as 80 mutated genes per colorectal tumor, but a smaller group of mutations (<15) were considered to be the true “drivers” of tumorigenesis (Wood et al 2007; Leary et al 2008). Genomic instability is recognized as an essential cellular feature that accompanies the acquisition of these mutations. In colorectal cancer, at least 3 distinct pathways of genomic instability have been described: the chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) pathways. The CIN pathway underlies the majority of all colorectal cancers. CIN is observed in 65%-70% of sporadic colorectal cancers; the term refers to an accelerated rate of gains or losses of whole or large portions of chromosomes that results in karyotypic variability from cell to cell (Lengauer et al 1998). The consequence of CIN is an imbalance in chromosome number (aneuploidy), sub-chromosomal genomic amplifications, and a high frequency of loss of heterozygosity (LOH).

Although the rich history of investigations and the identification of numerous genetic changes that are causative for CRC development, CRC is still a frequently lethal disease with heterogeneous outcomes and heterogeneous drug responses. To move to personalized medicine and thus to more effective treatment strategies, it would be advantageous to identify clinically relevant and molecularly homogeneous subtyping of CRC tumors. However subclassification perse, even when built on what are believed to be relevant features of cancer cells (such as expression of cancer pathway components or driver gene mutations), may still not be predictive of differential drug responses. This can be due to the drugs themselves, with promiscuous mechanisms of action that may not track well with single pathway descriptors, or to our inability to properly define pathway engagement or cross-talk using static ‘omics’ data. Recently a consensus gene expression-based subtyping classification system for CRC was identified by the CRC Subtyping Consortium (Guinney et al 2015). The published gene expression-based subtyping classification makes use of six independent classification systems to categorize CRC samples into one of the four consensus molecular subtypes (CMS). However, this classification can only sort 87% of the CRC samples. Still 13% of the samples do not fall within one of the four CMS groups and should be considered separately as indeterminate subtypes, of yet unknown biological and clinical behavior. Moreover none of the currently available gene expression based CRC sub-classification methods is predictive of one or more differential drug responses. To solve this problem we developed a new DNA sub-classification method based on copy number alterations (CNA) of specific DNA regions. The use of CNAs to classify cancer has been shown previously for e.g. non-small lung cancer (Li et al 2014), melanoma (WO2010/051319) and colorectal cancer (WO2010/051318). However, with the method described in this application we are not only using distinct DNA regions but we were also able to classify 100% of all tested metastatic CRC (mCRC) tumor samples in one of three different subgroups. Moreover the subgroups defined by this new DNA-based classification method are related with the patients' response to Avastin therapy. Avastin or bevacizumab is a frequently used anti-VEGF antibody for treating cancer (Ferrara et al 2004).

SUMMARY

Using copy number aberrations of specific DNA regions in a mCRC sample and subsequent unsupervised clustering we were able to classify mCRC tumors in 3 different subgroups. These subgroups are related with the patients' response to chemotherapy and outcome. Tumors that are classified in clusters 2 and 3 show additional benefit from Avastin treatment when compared to patients from the same clusters that received chemotherapy only. Hypermutator phenotypes, such as tumors with POLE or POLD1 mutations or micro-satellite instable tumors show no additional benefit from Avastin treatment. Copy number instability of specifically selected DNA regions is thus a biomarker for Avastin response. Tumors with a high proportion of the genome affected by CNAs have a significantly better response when treated with Avastin compared to copy number stable tumors.

It is an object of the invention to provide a colorectal cancer biomarker panel comprising at least 5 genomic DNA regions or fragments thereof selected from Table 1.

Another aspect of the invention is the use of said biomarker panel to determine the copy number alteration status of a colorectal cancer sample. The biomarker panel can also be used to determine the copy number instability of a colorectal cancer sample. According to particular embodiments, the biomarker panel comprising at least 5 genomic DNA regions or fragments thereof listed in Table 1, is used to cluster colorectal cancer samples in 3 distinct genetic subtypes wherein said subtypes are characterized by the copy number alteration specifications depicted in Tables 2, 3 and 4. According to particular embodiments, the said biomarker panel of the invention is used to predict the responsiveness of a colorectal cancer patient to anti-VEGF therapy.

According to another aspect a method is provided for determining the genetic subtype of a colorectal cancer sample, comprising determining the copy number alteration status of a colorectal cancer sample of a colorectal cancer patient using a biomarker panel, comprising at least 5 genomic DNA regions or fragments thereof selected from Table 1; and classifying said colorectal cancer sample in one of 3 distinct genetic subtypes wherein said subtypes are characterized by the copy number alteration specifications depicted in Tables 2, 3 and 4. According to particular embodiments, said method for determining the genetic subtype of a colorectal cancer sample can also be used to identify a patient responsive to anti-VEGF therapy, wherein classification of said patient in genetic subtypes 2 or 3 respectively depicted in Table 3 or 4 is indicative for said patient to be responsive to anti-VEGF therapy.

According to another aspect, a method is provided for the identification of a patient responsive to anti-VEGF therapy comprising determining the copy number instability of a CRC sample of a CRC patient using the biomarker panel comprising at least 5 genomic DNA regions or fragments thereof selected from Table 1, wherein a copy number instability of 15% or more is indicative for said patient to be responsive to anti-VEGF therapy.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Recurrent CNAs in primary and metastatic colorectal cancer. Recurrent amplifications (red) and deletions (blue) are represented. Focal amplifications are presented in (a), focal deletions in (b) and whole-arm amplifications and deletions in (c). The green lines represent the significance threshold at q<0.25. In total 43 recurrent focal amplifications and 59 focal deletions were identified.

FIG. 2. Unsupervised hierarchical consensus clustering of copy number profiles of primary and metastatic colorectal cancer (n=880). (a) Unsupervised hierarchical clustering classified tumors into 3 consensus CNA subgroups termed clusters 1-3 based on recurrent CNAs as determined by GISTIC. Presence of recurrent amplifications (red) and deletions (blue) for each sample are represented. (b-f) Genomic characterization of the 3 clusters revealed that cluster 1 was enriched for MSI tumors and hypermutators as well as tumors with mutations in BRAF and PIK3CA. In contrast, Clusters 2 and 3 were enriched for tumors with mutations in TP53, a high copy number instability and a higher number of chromosomal breakpoints. Mutations in KRAS and APC are found across all clusters.

FIG. 3. Kaplan Meier plots and univariate and multivariate correlation of the different clusters with PFS in primary and metastatic colorectal cancer. (a) Cluster 1 correlates with better survival compared to clusters 2 and 3. (b) However, multivariate analysis correcting for relevant covariates showed that not the cluster but primary tumor, regional lymph nodes and distant metastases staging are the main contributors to worse prognosis.

FIG. 4. Clinical characteristics of the different clusters in primary and metastatic colorectal cancer. Characterizing of the clusters on a clinical level revealed that clusters 2 and 3 were enriched for tumors with higher regional lymph nodes and distant metastases staging.

FIG. 5. Unsupervised hierarchical Ward consensus clustering of copy number profiles of metastatic colorectal cancer (n=444). (a) Unsupervised hierarchical clustering performed on the metastatic tumors only classified tumors into 3 consensus CNA subgroups termed clusters 1-3 based on recurrent CNAs as determined by GISTIC. Presence of recurrent amplifications (red) and deletions (blue) for each sample are represented. (b-f) Genomic characterization of the 3 clusters revealed that the characteristics of the clusters are almost identical to the clusters determined in primary and metastatic colorectal cancer combined. Cluster 1 was enriched for MSI tumors and hypermutators as well as tumors with mutations in BRAF and PIK3CA. In contrast, Clusters 2 and 3 were enriched for tumors with mutations in TP53, a high copy number instability and a higher number of chromosomal breakpoints. Mutations in KRAS and APC are found across all clusters.

FIG. 6. Kaplan Meier plots and univariate and multivariate cox-regression of progression free and overall survival of the different clusters. Kaplan Meier plots (a) and univariate and multivariate analysis (b) for progression free survival and Kaplan Meier plots (c) and univariate and multivariate analysis (d) for overall survival are presented. Clusters 1 correlates with worse survival, clusters 2 and 3 with better survival. This effect is independent of clinical factors such as age, gender and TNM-staging.

FIG. 7. Clinical characteristics of the different clusters in metastatic colorectal cancer. Characterisation of the clusters revealed no enrichment for particular clinical characteristics.

FIG. 8. Comparison of patients treated with Avastin to those not treated with Avastin for each of the clusters and the effect on PFS. Patients from clusters 2 (b) and 3 (c) show additional benefit when treated with Avastin compared to patients not treated with Avastin. No such effect is observed for patients from cluster 1 (a). Similar results were obtained when combining patients from clusters 2 and 3 in one group (d).

FIG. 9. Comparison of patients treated with Avastin to those not treated with Avastin for each of the clusters and the effect on OS. Patients from cluster 3 (c) show additional benefit when treated with Avastin compared to patients not treated with Avastin. No such effect is observed for patients from cluster 1 (a) and 2 (b). When combining patients from cluster 2 and 3 an additional benefit is observed albeit less pronounced than patients from cluster 3 alone (d).

FIG. 10. Comparison of CNA-high with CNA-low tumors. Patients were stratified in CNA-high and CNA-low tumors based on the proportion of genomic regions that are affected by CNAs. CNA-high tumors are defined as having more affected regions than the first quartile, CAN-low is defined as equal or less. CNA-high patients that are treated with Avastin have a significantly better progression free survival and overall compared to CNA-high patients treated with standard-of-care chemotherapy (a). This effect is not observed for CNA-low tumors (b). For the Avastin treated tumors, a higher proportion of the genome affected by CNAs correlates with a higher progression-free survival and overall survival compared to to tumors with a lower proportion of the genome (c). This effect is not present for tumors not treated with Avastin (d).

FIG. 11. Unsupervised hierarchical Ward consensus clustering of copy number profiles of primary and metastatic colorectal cancer (n=880) using only the focal amplifications and deletions. Unsupervised hierarchical clustering using only the focal regions classified tumors into 3 consensus CNA subgroups that are nearly identical compared to clustering using all 180 regions. (a) Kaplan Meier plots of overall survival for the 3 clusters. (b) Multivariate analysis correcting for relevant covariates again showed that not the cluster but primary tumor, regional lymph nodes and distant metastases staging are the main contributors to worse prognosis. (c-g) Genomic characterization of the 3 clusters revealed that cluster 1 was enriched for MSI tumors and hypermutators as well as tumors with mutations in BRAF and PIK3CA. In contrast, Clusters 2 and 3 were enriched for tumors with mutations in TP53, a high copy number instability and a higher number of chromosomal breakpoints. Mutations in KRAS and APC are found across all clusters.

FIG. 12. Kaplan Meier plots and univariate and multivariate cox-regression of progression free and overall survival of the different clusters in metastatic colorectal cancer using only the focal amplifications and deletions. Clusters 1 correlates with worse survival, clusters 2 and 3 with better survival. This effect is independent of clinical factors such as age, gender and TNM-staging.

FIG. 13. Comparison of patients treated with Avastin to those not treated with Avastin for each of the clusters and the effect on PFS using only focal amplifications and deletions. Patients from clusters 2 (b,f) and 3 (c,g) show additional benefit when treated with Avastin compared to patients not treated with Avastin. No such effect is observed for patients from cluster 1 (a,e). Similar results were obtained when combining patients from clusters 2 and 3 in one group (d,h).

FIG. 14. Comparison of patients treated with Avastin to those not treated with Avastin for each of the clusters and the effect on OS using only focal amplifications and deletions. Patients from cluster 3 (c,g) show additional benefit when treated with Avastin compared to patients not treated with Avastin. No such effect is observed for patients from cluster 1 (a,e) and 2 (b,f). When combining patients from cluster 2 and 3 an additional benefit is observed albeit less pronounced than patients from cluster 3 alone (d,h).

FIG. 15. Accuracy of the different tiers identified using recursive partitioning analysis. (a) Boxplot of the accuracies of all trees generated using the different tiers starting from all 180 genomic regions. (b) Boxplot of the accuracies of all tree generated using the different tiers starting from the 102 focal genomic regions.

FIG. 16. K-nearest neighbors classification and random forest classification results on the replication cohort generated using all 180 genomic regions. Application of both the k-nearest neighbors classification model (a) and the random forest classification model (b) to the replication cohort classified the samples in 3 different clusters with very similar characteristics as the original clustered obtained from hierarchical clustering in terms of proportion of the genome affected by CNAs and number of breakpoints. Similar as the original clustering results cluster 2 and 3 show improved progression free survival.

FIG. 17. K-nearest neighbors classification and random forest classification results on the replication cohort generated using the 102 focal genomic regions. Application of both the k-nearest neighbors classification model (a) and the random forest classification model (b) to the replication cohort classified the samples in 3 different clusters with very similar characteristics as the original clustered obtained from hierarchical clustering in terms of proportion of the genome affected by CNAs and number of breakpoints. Similar as the original clustering results cluster 2 and 3 show improved progression free survival.

FIG. 18. Comparison of CNA-high with CNA-low tumors using only the 102 focal regions. Similar as the analysis for FIG. 10 we stratified patients in CNA-high and low and determined the relation with response to Avastin therapy. CNA-high tumors of patients treated with Avastin show a significant increase in progression free (a) and overall survival (c) compared to patients treated with standard-of-care chemotherapy. No such effect was noted for CNA-low tumors (b,d).

FIG. 19. Comparison of CNA-high with CNA-low tumors using the tier 1 and tier 2 regions from the recursive partitioning applied on the 102 focal regions. Similar as the analysis for FIG. 10 we stratified patients in CNA-high and low and determined the relation with response to Avastin therapy. CNA-high tumors of patients treated with Avastin show a significant increase in progression free (a) and overall survival (c) compared to patients treated with standard-of-care chemotherapy. No such effect was noted for CNA-low tumors (b,d).

FIG. 20. Comparison of CNA-high with CNA-low tumors using the tier 1 and tier 2 regions from the recursive partitioning applied all 180 regions. Similar as the analysis for FIG. 10 we stratified patients in CNA-high and low and determined the relation with response to Avastin therapy. CNA-high tumors of patients treated with Avastin show a significant increase in progression free (a) and overall survival (c) compared to patients treated with standard-of-care chemotherapy. No such effect was noted for CNA-low tumors (b,d).

FIG. 21. Comparison of CNA-high with CNA-low tumors using the top 50 ranked regions from the random forest classification model built with the 102 focal regions. Similar as the analysis for FIG. 10 we stratified patients in CNA-high and low and determined the relation with response to Avastin therapy. CNA-high tumors of patients treated with Avastin show a significant increase in progression free (a) and overall survival (c) compared to patients treated with standard-of-care chemotherapy. No such effect was noted for CNA-low tumors (b,d).

FIG. 22. Comparison of CNA-high with CNA-low tumors using the top 50 ranked regions from the random forest classification model built with the 180 focal regions. Similar as the analysis for FIG. 10 we stratified patients in CNA-high and low and determined the relation with response to Avastin therapy. CNA-high tumors of patients treated with Avastin show a significant increase in progression free (a) and overall survival (c) compared to patients treated with standard-of-care chemotherapy. No such effect was noted for CNA-low tumors (b,d).

FIG. 23. Classification of tumors in CNA-high or CNA-low for the avastin-treated replication cohort. Similar as the analysis for FIG. 10 we stratified patients in CNA-high and CNA-low (with the thresholds set to 30% and 25% for the top 50 ranking regions from the random forest classifiers (a,b) and the tier 1 and 2 regions (c,d) for both only focal regions (b,c) and all 180 regions (a,c) respectively. For each of the different subsets of genomic regions CNA-high tumors showed an increased progression free survival.

FIG. 24. The effect is independent from MSI status. To investigate whether the irresponsiveness of patients from cluster 1 to Avastin therapy was caused by tumors that show microsatellite instability we stratified patients from cluster 1 in MSI (a) and microsatellite stable (MSS) patients (b) and determined the relation with response to Avastin therapy. No difference between the samples was observed indicating that copy number stable samples that are MSS show no improved response on Avastin therapy and the effect is not solely dependent on MSI.

DETAILED DESCRIPTION Definitions

The present invention will be described with respect to particular embodiments and with reference to certain drawings but the invention is not limited thereto but only by the claims. Any reference signs in the claims shall not be construed as limiting the scope. The drawings described are only schematic and are non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn on scale for illustrative purposes. Where the term “comprising” is used in the present description and claims, it does not exclude other elements or steps. Where an indefinite or definite article is used when referring to a singular noun e.g. “a” or “an”, “the”, this includes a plural of that noun unless something else is specifically stated. Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein. The following terms or definitions are provided solely to aid in the understanding of the invention. Unless specifically defined herein, all terms used herein have the same meaning as they would to one skilled in the art of the present invention. Practitioners are particularly directed to Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Press, Plainsview, N.Y. (2012); and Ausubel et al., current Protocols in Molecular Biology (Supplement 100), John Wiley & Sons, New York (2012), for definitions and terms of the art. The definitions provided herein should not be construed to have a scope less than understood by a person of ordinary skill in the art.

In a first aspect, the invention relates to a colorectal cancer biomarker panel for determining the copy number alteration status of a colorectal cancer sample, comprising at least 5 genomic DNA regions or fragments thereof selected from Table 1. It also relates to a colorectal cancer biomarker panel for determining the copy number instability of a CRC sample comprising at least 5 genomic DNA regions or fragments thereof selected from Table 1. In a particular embodiment, said biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Table 5. In a more particular embodiment, said biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Table 6. In an even more particular embodiment, said biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Table 10.

The term “colorectal cancer biomarker panel” as used herein, and from hereon also referred to as “biomarker panel”, means a limited list of genomic DNA regions which can be used to determine the copy number alteration status or the copy number instability of a CRC sample. Importantly, although all genomic DNA regions listed in Table 1 are valuable and can be used as markers to evaluate copy number instability of CRC samples, it does not imply that all regions are needed to classify a CRC sample as copy number stable or unstable. Depending on the classification method used and the % accuracy the practitioner aims for, subselections of the listed genomic DNA regions can be used. In this application, Applicant teaches that a selection of 5 from the 180 genomic DNA regions listed in Table 1 can be enough to cluster CRC samples and thus to determine whether a CRC sample is copy number stable or instable with a high accuracy. Accordingly, CRC biomarker panel comprising “at least 5 genomic DNA regions” is envisaged in the embodiments described above. In alternative embodiments, the colorectal cancer biomarker panel of the application comprises at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12 or at least 20 genomic DNA regions or fragments thereof selected from Table 1 or from Table 5 or from Table 6 or from Table 10. In other alternative embodiments, a colorectal cancer biomarker panel is provided comprising at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12 or at least 20 genomic DNA regions or fragments thereof selected from the genomic DNA regions listed in Table 6 and Table 7 or from the genomic DNA regions listed in Table 10 and Table 11.

The term “genomic DNA region” as used herein means a DNA sequence that is part of the genome of a cell or organism, as distinguished from extrachromosomal DNA, such as plasmids. The genomic DNA regions which are used within the scope of this invention are listed in Table 1. For every genomic DNA region within the scope of this application, Table 1 and Table 5 show the “wide peak limits” and the “peak limits”. The “wide peak limits” indicate the full sequence which contains the most comprehensive information. However, the invention also relates to smaller fragments of the listed genomic DNA regions. The “peak limits” for example indicate a subregion within the “wide peak limits” which contains the most condensed information to determine the copy number alteration status or copy number instability. Even smaller fragments within the “peak limits” can be used to cluster CRC samples according to the methods of the invention or can be used to determine the genetic subtype of CRC samples according to the methods of the invention or can be used to determine copy number instability of CRC samples according to the methods of the invention. Thus also smaller fragments which are part of the listed genomic DNA regions of Table 1 or Table 5 and which for example can be amplified by PCR or detected with probes related to DNA detection techniques (e.g. Southern blot) fall within the scope of the invention. Hence, the “biomarker panel” has to be read as comprising at least 5 genomic DNA regions listed in Table 1 or Table 5 or fragments thereof. Said fragments are thus smaller DNA fragments that are part of said genomic DNA regions. However, the said fragments of the at least 5 genomic DNA regions still need to have predictive power to determine the CNA status of a CRC sample, to determine the CIN of a CRC sample, to be useful to cluster CRC samples into the 3 genetic subtypes of the invention, to predict the responsiveness of a CRC patient to anti-VEGF therapy, to determine the genetic subtypes of the invention and/or to identify patients responsive to anti-VEGF therapy.

The term “copy number alterations” or “copy number aberrations”, both abbreviated as CNAs and interchangeably used in this application, are changes in copy number of specific DNA regions whereby the changes have arisen in somatic tissue, for example, only in a tumor. These changes can be amplifications or deletions. The “copy number alteration status” is thus the level or number of changes in copy number of a predefined list of DNA regions. For example, tumors can be categorized in CNA-high tumors and CNA-low tumors.

The relative number of regions affected by CNAs can be seen as a measure for copy number instability. Using different thresholds to define tumors as copy number unstable and stratify the patients accordingly we were able to observe beneficial responses to Avastin treatment for tumor instabilities ranging from 10% to 40% of regions affected by CNAs. We performed this analysis on 6 different subsets (1) using only the 102 focal regions, (2) using the top 50 ranked regions from the random forest classification model built with the 102 focal regions, (3) using the tier 1 and tier 2 regions from the recursive partitioning applied on the 102 focal regions, (4) using all 180 genomic regions (5) using the tier 1 and tier 2 regions from the recursive partitioning applied all 180 regions and (6) using the top 50 ranked regions from the random forest classification model built with the 180 focal regions.

In this application, CNA-high tumors are defined as tumors in which preferably 10% or more, more preferably 15% or more of the DNA region consisting of the biomarker panel used for the analysis (i.e. the genomic regions selected from Table 1 or Table 5 or fragments thereof that were used to determine the CNAs) is affected by CNAs, more preferably in which 20% or more of the DNA region consisting of the biomarker panel used for the analysis (i.e. the genomic regions selected from Table 1 or Table 5 or fragments thereof that were used to determine the CNAs) is affected by CNAs, and most preferably in which 26% or more of the DNA region consisting of the biomarker panel used for the analysis (i.e. the genomic regions selected from Table 1 or Table 5 or fragments thereof that were used to determine the CNAs) is affected by CNAs. For example, if 6 of the 180 genomic regions listed in Table 1 or Table 5 or fragments thereof are used to classify a CRC sample into one of the three genetic subtypes, then “x % or more of the DNA sequence consisting of the biomarker panel used for the analysis” means x % or more of the DNA sequence consisting of the 6 used genomic regions or fragments thereof. Similarly, if 10 of the 180 genomic regions listed in Table 1 or Table 5 or fragments thereof are used to classify a CRC sample into one of the three genetic subtypes, then “x % or more of the DNA sequence consisting of the biomarker panel used for the analysis” means x % or more of the DNA sequence consisting of the 10 used genomic regions or fragments thereof. A CNA-high tumor is thus copy number instable and therefore also referred to as “copy number instability high tumor” or CIN-high tumor. CNA-low tumors as used herein are tumors in which less than 15% of the DNA sequence consisting of the biomarker panel used for the analysis (i.e. the genomic regions selected from Table 1 or Table 5 or fragments thereof that were used to determine the CNAs) is affected by CNAs. Thus, if 6 of the 180 genomic regions listed in Table 1 or Table 5 or fragments thereof are used to classify a CRC sample into one of the three genetic subtypes, than less than 15% of the DNA sequence consisting of the 6 used genomic regions or fragments thereof is affected by CNA's to categorize the tumor as CNA-low. In alternative embodiments, CNA-low tumors as used herein are tumors in which less than 10% of the DNA sequence consisting of the biomarker panel used for the analysis (i.e. the genomic regions selected from Table 1 or Table 5 or fragments thereof that were used to determine the CNAs) is affected by CNAs. A CNA-low tumor has thus a low copy number instability and therefore also referred to as “copy number instability low tumor” or CIN-low tumor. Copy number alterations or copy number aberrations are not the same as copy number variations (CNVs). CNVs originate from changes in copy number in germline cells (and are thus in all cells of the organism).

The term “colorectal cancer” as used herein is meant to include malignant neoplasms of colon (C18 in ICD-10), malignant neoplasms of rectosigmoid junction (C19 in ICD-10), malignant neoplasms of rectum (C20 in ICD-10) and malignant neoplasms of anus and anal canal (C21 in ICD-10). A “colorectal cancer sample” refers to a biological sample of a “colorectal cancer patient”. A “colorectal cancer patient” refers to a living subject diagnosed with colorectal cancer or suspected to have colorectal cancer. In case that colorectal cancer is diagnosed with a living subject, a CRC sample comprises at least one colorectal cancer cell.

The 180 genomic DNA regions or fragments thereof which are listed in Table 1 or the 102 genomic DNA regions of fragments thereof which are listed in Table 5 are DNA regions which can be used to evaluate the copy number alteration status of a CRC sample and thus whether a colorectal cancer sample is copy number stable or instable or which can be used to cluster CRC samples (explained below). Although all 180 genomic DNA regions or fragments thereof are all informative and as valuable, some have a larger impact on the outcome of the analysis. In first instance, the impact of deletions or amplifications of specific genomic DNA regions on the evaluation of the copy number instability or of the copy number alteration status of a CRC sample depends on the classification method used. In current application, Applicant has confirmed the relevance of all 180 genomic DNA regions listed in Table 1 and of all 102 genomic DNA regions listed in Table 5 with three different methods, i.e. using regression trees, using the random forest classification and using the K-nearest neighbour classification (see Example 7). Another reason for the genomic DNA region dependent impact, is that some mutations affecting the copy number of specific genomic DNA regions occur early in colorectal tumor development, while other mutations occur at a later stage. However, the observation that copy number alterations of some genomic DNA regions have more or less impact does not mean that selecting genomic DNA regions with less impact is not useful to cluster CRC samples. All the genomic DNA regions listed in Table 1 are as valuable. The impact of selecting DNA regions with less strength might be that more of these regions will have to be used in the analysis to achieve the same level of accuracy.

Depending on the analysis method, different subselections can be made from the 180 genomic DNA regions or fragments thereof listed in Table 1 or from the 102 genomic DNA regions or fragments thereof listed in Table 5.

Therefore, in a particular embodiment of the first aspect, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Tables 6, 7, 8 and/or 9, wherein at least 2 genomic DNA regions or fragments thereof are selected from Table 6. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Tables 6, 7, 8 and/or 9, wherein at least 3, at least 4 or at least 5 genomic DNA regions or fragments thereof are selected from Table 6. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 6 genomic DNA regions or fragments thereof selected from Tables 6, 7, 8 and/or 9, wherein at least 2, at least 3, at least 4, at least 5 or at least 6 genomic DNA regions or fragments thereof are selected from Table 6.

In another particular embodiment of the first aspect, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Tables 6, 7 and/or 8, wherein at least 2 genomic DNA regions or fragments thereof are selected from Table 6. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Tables 6, 7 and/or 8, wherein at least 3, at least 4 or at least 5 genomic DNA regions or fragments thereof are selected from Table 6. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 6 genomic DNA regions or fragments thereof selected from Tables 6, 7 and/or 8, wherein at least 2, at least 3, at least 4, at least 5 or at least 6 genomic DNA regions or fragments thereof are selected from Table 6.

In another particular embodiment of the first aspect, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Tables 6 and/or 7, wherein at least 2 genomic DNA regions or fragments thereof are selected from Table 6. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Tables 6 and/or 7, wherein at least 3, at least 4 or at least 5 genomic DNA regions or fragments thereof are selected from Table 6. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 6 genomic DNA regions or fragments thereof selected from Tables 6 and/or 7, wherein at least 2, at least 3, at least 4, at least 5 or at least 6 genomic DNA regions or fragments thereof are selected from Table 6.

In another particular embodiment of the first aspect, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Tables 6 and/or 7. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 or at least 12 genomic DNA regions or fragments thereof selected from Tables 6 and/or 7.

In yet another particular embodiment of the first aspect, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Tables 10, 11 and/or 12, wherein at least 2 genomic DNA regions or fragments thereof are selected from Table 10. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Tables 10, 11 and/or 12, wherein at least 3, at least 4 or at least 5 genomic DNA regions or fragments thereof are selected from Table 10. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 6 genomic DNA regions or fragments thereof selected from Tables 10, 11 and/or 12, wherein at least 2, at least 3, at least 4, at least 5 or at least 6 genomic DNA regions or fragments thereof are selected from Table 10.

In another particular embodiment of the first aspect, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Tables 10 and/or 11, wherein at least 2 genomic DNA regions or fragments thereof are selected from Table 10. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Tables 10 and/or 11, wherein at least 3, at least 4 or at least 5 genomic DNA regions or fragments thereof are selected from Table 10. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 6 genomic DNA regions or fragments thereof selected from Tables 10 and/or 11, wherein at least 2, at least 3, at least 4, at least 5 or at least 6 genomic DNA regions or fragments thereof are selected from Table 10.

In another particular embodiment of the first aspect, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions or fragments thereof selected from Tables 10 and/or 11. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 or at least 12 genomic DNA regions or fragments thereof selected from Tables 10 and/or 11.

Using the random forest classification method, a contribution value could be determined for every genomic DNA region listed in Table 1 or Table 5. The contribution value illustrates the importance of a CNA for correct classification of a sample. For each tree, the prediction error rate on the out-of-bag portion of the data is recorded. Then the same is done after permuting each predictor variable. The difference between the two are then averaged over all trees, and normalized by the standard deviation of the differences.

Therefore, in a particular embodiment of the first aspect, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions selected from Table 13, wherein said at least 5 genomic DNA regions have a contribution value of at least 1, at least 2, at least 3, at least 4 or at least 5 as listed in Table 13. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 6 genomic DNA regions selected from Table 13, wherein said at least 6 genomic DNA regions have a contribution value of at least 1, at least 2, at least 3, at least 4 or at least 5 as listed in Table 13.

In another particular embodiment, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions selected from Table 13, wherein at least 2, at least 3, at least 4 or at least 5 genomic DNA regions from said at least 5 genomic DNA regions have a contribution value between 1 and 6 or between 2 and 6 or between 3 and 6 or between 4 and 6 or between 1 and 5 or between 2 and 5 or between 3 and 5 or between 2 and 4 as listed in Table 13.

In another particular embodiment, said colorectal cancer biomarker panel comprises at least 6 genomic DNA regions selected from Table 13, wherein at least 2, at least 3, at least 4, at least 5 or at least 6 genomic DNA regions from said at least 6 genomic DNA regions have a contribution value between 1 and 6 or between 2 and 6 or between 3 and 6 or between 4 and 6 or between 1 and 5 or between 2 and 5 or between 3 and 5 or between 2 and 4 as listed in Table 13.

In yet another particular embodiment, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions selected from Table 14, wherein said at least 5 genomic DNA regions have a contribution value of at least 1, at least 2, at least 3, at least 4, at least 7, at least 8 or at least 9 as listed in Table 14. In another particular embodiment, said colorectal cancer biomarker panel comprises at least 6 genomic DNA regions selected from Table 14, wherein said at least 6 genomic DNA regions have a contribution value of at least 1, at least 2, at least 3, at least 4, at least 7, at least 8 or at least 9 as listed in Table 14.

In another particular embodiment, said colorectal cancer biomarker panel comprises at least 5 genomic DNA regions selected from Table 14, wherein at least 2, at least 3, at least 4 or at least 5 genomic DNA regions from said at least 5 genomic DNA regions have a contribution value between 2 and 10 or between 3 and 10 or between 4 and 10 or between 7 and 10 or between 2 and 8 or between 3 and 8 or between 4 and 8 as listed in Table 14.

In another particular embodiment, said colorectal cancer biomarker panel comprises at least 6 genomic DNA regions selected from Table 14, wherein at least 2, at least 3, at least 4, at least 5 or at least 6 genomic DNA regions from said at least 6 genomic DNA regions have a contribution between 2 and 10 or between 3 and 10 or between 4 and 10 or between 7 and 10 or between 2 and 8 or between 3 and 8 or between 4 and 8 as listed in Table 14.

In yet other embodiments, said colorectal cancer biomarker panel comprises at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 120, at least 140 or at least 160 genomic DNA regions selected from Table 1. In a most particular embodiment, said colorectal cancer biomarker panel consist of the genomic DNA regions depicted in Table 1.

In yet other embodiments, said colorectal cancer biomarker panel comprises at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 genomic DNA regions selected from Table 5.

In most particular embodiments, said colorectal cancer biomarker panel consist of the genomic DNA regions depicted in Table 10, in Table 10 and Table 11, in Table 6 or in Table 6 and Table 7. In another most particular embodiment, said colorectal cancer biomarker panel consist of the genomic DNA regions depicted in Table 5 or in Table 1.

The colorectal cancer biomarker panels disclosed above in the first aspect of this application are from here on referred as “one of the colorectal cancer biomarker panels disclosed in one of the embodiments of the first aspect of the application” or as “one of the colorectal cancer biomarker panels of the application”.

In a second aspect, the invention relates to the use of a biomarker panel comprising at least 5 or at least 6 genomic DNA regions or fragments thereof selected from Table 1 to determine the copy number alteration status of a colorectal cancer sample. The invention also relates to the use of said biomarker panel to predict copy number instability of a colorectal cancer sample of a CRC patient. In particular embodiments, said Table 1 is Table 5, Table 6 or Table 10. In other particular embodiments, the use of a biomarker panel is provided for determining the copy number alteration status of a CRC sample or the copy number instability of a CRC sample, wherein said biomarker panel is one of the colorectal cancer biomarker panels disclosed in one of the embodiments of the first aspect of the application described above.

“Copy number instability” as used herein is defined as the gain and/or loss of copies of a specific set of genomic DNA regions. In a more particular embodiment, the invention relates to the use of one of the colorectal cancer biomarker panels of the application to classify a colorectal cancer sample of a CRC patient in a copy number instability (CIN) high or copy number instability low group. Copy number instability-high sample is defined as a sample in which 10%, preferable 15% or more of the DNA region consisting of the biomarker panel used for the analysis (e.g. the genomic regions selected from Table 1 or fragments thereof that were used to determine the CNAs) is affected by copy number alterations, more preferably 20% or more of the DNA region consisting of the biomarker panel used for the analysis (e.g. the genomic regions selected from Table 1 or fragments thereof that were used to determine the CNAs) is affected by CNAs and most preferably 26% or more of the DNA region consisting of the biomarker panel used for the analysis (e.g. the genomic regions selected from Table 1 or fragments thereof that were used to determine the CNAs) is affected by CNAs. This is especially important since our data surprisingly revealed that patients' samples with a high copy number instability are responsive to anti-VEGF therapy. To investigate whether the irresponsiveness of patients from cluster 1 to Avastin therapy was caused by tumors that show microsatellite instability we stratified patients from cluster 1 in MSI (a) and microsatellite stable (MSS) patients (b) and determined the relation with response to Avastin therapy. No difference between the samples was observed indicating that copy number stable samples that are MSS show no improved response on Avastin therapy and the effect is not solely dependent on MSI. In an alternative embodiment, a CIN-low sample is defined as a sample in which less than 10% of the DNA region consisting of the biomarker panel used for the analysis (e.g. the genomic regions selected from Table 1 or fragments thereof that were used to determine the CNAs) is affected by CNAs.

In a third aspect, the invention relates to the use of a biomarker panel comprising at least 5 or at least 6 genomic DNA regions or fragments thereof selected from Table 1 to cluster colorectal cancer samples in distinct genetic subtypes, wherein said subtypes are constructed using a dataset of multiple CRC samples. In a particular embodiment, said Table 1 is Table 5, Table 6 or Table 10. In another particular embodiment, the use of a biomarker panel to cluster colorectal cancer samples in distinct genetic subtypes is provided, wherein said subtypes are constructed using a dataset of multiple CRC samples and wherein said biomarker panel is one of the colorectal cancer biomarker panels disclosed in one of the embodiments of the first aspect of the application described above. More particular said biomarker panel comprises at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 genomic regions or fragments thereof selected from Table 1 or Table 5. Even more particularly, said biomarker panel comprises at least 120, at least 130, at least 140, at least 150, at least 160 or at least 170 genomic regions or fragments thereof selected from Table 1. Most particularly, said biomarker panel consists of the genomic regions or fragments thereof selected from Table 1.

Dataset of multiple CRC samples are free available and are accessible to the person skilled in the art. In a preferred embodiment, said dataset consist of at least 100 CRC samples, more preferably at least 200 CRC samples, more preferably at least 300 CRC samples, most preferably at least 400 CRC samples.

In a particular embodiment, the use of a biomarker panel to cluster colorectal cancer samples in distinct genetic subtypes is provided, wherein said subtypes are constructed using a dataset of multiple CRC samples and wherein said biomarker panel is one of the colorectal cancer biomarker panels disclosed in one of the embodiments of the first aspect of the application described above, and wherein said subtypes are constructed using unsupervised hierarchical clustering. In a more particular embodiment, said subtypes are characterized by the copy number alteration specifications depicted in Tables 2, 3 and 4.

Using the means and methods of current application, 3 distinct genetic subtypes were determined, however depending on the clustering method and preferences of the practitioner more or less genetic subtypes can be constructed using the biomarker panel of the invention. In another particular embodiment, the use of a biomarker panel to cluster colorectal cancer samples in 3 distinct genetic subtypes is provided, wherein said subtypes are characterized by the copy number alteration specifications depicted in Tables 2, 3 and 4, wherein said biomarker panel is one of the colorectal cancer biomarker panels disclosed in one of the embodiments of the first aspect of the application described above.

The term “genetic subtype” as used herein means a category of CRC samples having common genetic characteristics, more precisely having a common copy number alteration status. “Distinct” means different, separate or diverse. In the application “genetic subtype” refers to a specific cluster. Cluster 1, 2, 3 are thus respectively the same as genetic subtype 1, 2, 3. The term “copy number alteration specifications” as used herein means the conditions to which a genetic sample must comply to fall into one of the genetic subtypes described in this application.

In another embodiment, the use of a biomarker panel is provided to predict the responsiveness of a colorectal cancer patient to anti-VEGF therapy, wherein said biomarker panel is one of the colorectal cancer biomarker panels disclosed in one of the embodiments of the first aspect of the application described above. The invention thus also relates to the use of the biomarker panel comprising at least 5 or at least 6 genomic DNA regions or fragments thereof selected from Table 1 or Table 5 to predict the responsiveness of a colorectal cancer patient to anti-VEGF therapy. In a more particular embodiment, said anti-VEGF therapy is bevacizumab therapy.

This is equivalent as saying that the biomarker panels described in the first aspect of the application or more particularly the biomarker panel comprising at least 5 genomic DNA regions or fragments thereof selected from Table 1 or Table 5 are provided for use in diagnosis of a CRC patient with responsiveness to anti-VEGF therapy, where in a particular embodiment said anti-VEGF therapy is bevacizumab therapy.

“Responsiveness” is defined in this application as the reaction or response of a CRC patient to an anti-VEGF treatment, more precisely to bevacizumab therapy. The response is positive or the patient is responsive to anti-VEGF therapy if the treatment clinically improves the situation of the patient. The term “anti-VEGF therapy” as used herein refers to an anti-angiogenic therapy, i.e. a therapy for example a medicament that inhibits angiogenesis or the growth of new blood vessels. VEGF stands for vascular endothelial growth factor and is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. Bevacizumab or avastin is a frequently used anti-VEGF antibody for treating cancer.

Bevacizumab and avastin are interchangeably used in this application. “Bevacizumab therapy” thus refers to the treatment of a patient that comprises bevacizumab administration. Bevacizumab can be administered as monotherapy or as combination therapy. Typically, monotherapy is used to describe the use of a single medication, while combination therapy or polytherapy uses more than one medication. A pharmacological therapy (i.e. a therapy that consists of one or more medicament against a single disease) can also be combined with other non-pharmacological therapies as radiation therapy and surgery.

In a fourth aspect, a method is provided to determine the genetic subtype of a colorectal cancer sample from a colorectal cancer patient, said method comprises:

-   -   a. Clustering a dataset of multiple CRC samples in distinct         genetic subtypes using one of the CRC biomarker panels disclosed         in one of the embodiments of the first aspect of current         application;     -   b. Classifying said CRC sample from said CRC patient in one of         said distinct genetic subtypes using one of the CRC biomarker         panels disclosed in one of the embodiments of the first aspect         of current application.

In particular embodiments, said clustering of step a) is done using a CRC biomarker panel comprising at least 5 genomic DNA regions or fragments thereof selected from Table 1 or Table 5 while said classification of step b) is done using the same said CRC biomarker panel.

The invention also provides a method for determining the genetic subtype of a colorectal cancer sample, comprising determining the copy number alteration status of a colorectal cancer sample of a colorectal cancer patient using one of the colorectal cancer biomarker panels described in the first aspect of the application (e.g. comprising at least 5 genomic DNA regions or fragments thereof selected from Table 1 or Table 5); classifying said colorectal cancer sample in one of 3 distinct genetic subtypes wherein said subtypes are characterized by the copy number alteration specifications depicted in Tables 2, 3 and 4; to determine the genetic subtype of said colorectal cancer sample.

“Classifying” means arranging a sample in a specific category (e.g. genetic subtype) according to shared qualities or characteristics with the other subjects of the specific category.

In a fifth aspect, the invention provides a method for the identification of a patient responsive to anti-VEGF therapy comprising determining the copy number alteration status of a colorectal cancer sample of a colorectal cancer patient using one of the colorectal cancer biomarker panels disclosed in one of the embodiments of the first aspect of this application (e.g. comprising at least 5 genomic DNA regions or fragments thereof selected from Table 1 or Table 5); classifying said colorectal cancer sample in one of 3 distinct genetic subtypes wherein said subtypes are characterized by the copy number alteration specifications depicted in Tables 2, 3 and 4 to determine the genetic subtype of said colorectal cancer sample, wherein classification of said patient in genetic subtypes 2 or 3 respectively depicted in Table 3 or 4 is indicative for said patient to be responsive to anti-VEGF therapy. In a more particular embodiment, the anti-VEGF therapy is bevacizumab therapy.

In a sixth aspect, the invention provides a method for the identification of a patient responsive to anti-VEGF therapy comprising:

-   -   Determining the copy number alteration status of a colorectal         cancer sample of said subject using a biomarker panel, wherein         said biomarker panel is one of the CRC biomarker panels         disclosed in the first aspect of the application;     -   Classifying said patient as responsive to anti-VEGF therapy, if         the copy number alteration status of the CRC sample of said         patient classifies the CRC sample as genetic subtype 2 or 3 of         which the copy number alteration specification are respectively         depicted in Table 3 or 4.

In a particular embodiment, the invention provides a method for the identification of a patient responsive to anti-VEGF therapy comprising:

-   -   Determining the copy number alteration status of a colorectal         cancer sample of said subject using a biomarker panel comprising         at least 5 or at least 6 genomic DNA regions or fragments         thereof selected from Table 1 or Table 5 or Table 6 or Table 10;     -   Classifying said patient as responsive to anti-VEGF therapy, if         the copy number alteration status of the CRC sample of said         patient classifies the CRC sample as genetic subtype 2 or 3 of         which the copy number alteration specification are respectively         depicted in Table 3 or 4.

In a more particular embodiment, the anti-VEGF therapy is bevacizumab therapy.

The term “indicative” as used herein means that a patient is predicted to be responsive to a therapy.

In another embodiment the invention provides a method for the identification of a patient responsive to anti-VEGF therapy, said method comprising determining the copy number instability of the genome of a CRC sample of a CRC patient, wherein a high copy number instability is indicative for said patient to be responsive to anti-VEGF therapy. The invention also provides methods for the identification of a patient responsive to anti-VEGF therapy, said methods comprising determining the copy number instability of a CRC sample of a CRC patient using one of the CRC biomarker panels disclosed in the first aspect of the application, wherein a high copy number instability is indicative for said CRC patient to be responsive to anti-VEGF therapy. The invention also provides methods for the identification of a patient responsive to anti-VEGF therapy, said methods comprising determining the copy number instability of a CRC sample of a CRC patient using a biomarker panel comprising at least 5 or at least 6 genomic DNA regions or fragments thereof selected from Table 1 or Table 5 or Table 6 or Table 10 wherein a high copy number instability is indicative for said CRC patient to be responsive to anti-VEGF therapy. In a more particular embodiment, the anti-VEGF therapy is bevacizumab therapy.

A high copy number instability means 10% or more, 15% or more, more preferably 20% or more, most preferably 26% or more of the DNA sequence consisting of the genomic regions or fragments thereof used for the analysis (e.g. those selected from Table 1 or Table 5) is affected by copy number alterations. The invention thus also provides methods for the identification of a patient responsive to anti-VEGF therapy comprising determining the copy number instability of a CRC sample of a CRC patient using one of the biomarker panels disclosed in the first aspect of the application or using a biomarker panel comprising at least 5 genomic DNA regions or fragments thereof selected from Table 1 or Table 5 or Table 6 or Table 10, wherein a copy number instability of 15% or more is indicative for said CRC patient to be responsive to anti-VEGF therapy or more particularly to bevacizumab therapy. The invention also provides methods for the identification of a patient responsive to anti-VEGF therapy comprising determining the copy number instability of the genome of a CRC sample of a CRC patient using one of the biomarker panels disclosed in the first aspect of the application or using a biomarker panel comprising at least 5 genomic DNA regions or fragments thereof selected from Table 1 or Table 5 or Table 6 or Table 10, wherein a copy number instability of 20% or more is indicative for said patient to be responsive to anti-VEGF therapy or more particularly to bevacizumab therapy. The invention also provides methods for the identification of a patient responsive to anti-VEGF therapy comprising determining the copy number instability of a CRC sample of a CRC patient using one of the biomarker panels disclosed in the first aspect of the application or using a biomarker panel comprising at least 5 genomic DNA regions or fragments thereof selected from Table 1 or Table 5 or Table 6 or Table 10, wherein a copy number instability of 26% or more is indicative for said CRC patient to be responsive to anti-VEGF therapy or more particularly to bevacizumab therapy.

In another embodiment, the invention provides a method for treating colorectal cancer in a subject in need thereof, comprising:

-   -   Determining the genetic subtype of a colorectal cancer sample of         said subject according to the method of the invention for         determining the genetic subtype of a colorectal cancer sample;     -   Administering anti-VEGF therapy to a subject, if the genetic         subtype of said sample of said subject is classified as genetic         subtype 2 or 3 of which the copy number alteration         specifications are respectively depicted in Table 3 or 4.

In a more particular embodiment, the anti-VEGF therapy is bevacizumab therapy.

In another embodiment, the invention provides a method of treating colorectal cancer in a subject in need thereof, comprising:

-   -   Determining the copy number alteration status of a colorectal         cancer sample of said subject using one of the biomarker panels         disclosed in the first aspect of this application or using a         biomarker panel comprising at least 5 genomic DNA regions or         fragments thereof selected from Table 1 or Table 5 or Table 6 or         Table 10;     -   Administering anti-VEGF therapy to said subject, if the copy         number alteration status of the CRC sample of said subject         classifies the CRC sample as genetic subtype 2 or 3 of which the         copy number alteration specifications are respectively depicted         in Table 3 or 4.

In a more particular embodiment, the anti-VEGF therapy is bevacizumab therapy.

“Respectively depicted” as used in the application means that the specifications of subtype 2 are shown in Table 3 and that of subtype 3 are presented in Table 4.

In another embodiment the invention provides a method of treating colorectal cancer in a subject in need thereof, comprising:

-   -   Determining the copy number instability of the genome of a CRC         sample of said subject wherein said sample comprises at least         one colorectal cancer cell;     -   Administering anti-VEGF therapy to a subject, if said sample of         said subject is characterized by a high copy number instability,         wherein a high copy number instability means that 15% or more of         said genome is affected by copy number alterations, wherein said         genome comprises the genomic regions used for the analysis and         selected from Table 1 or Table 5 or Table 6 or Table 10.

In a more particular embodiment, the anti-VEGF therapy is bevacizumab therapy.

In another embodiment the invention provides a method of treating colorectal cancer in a subject in need thereof, comprising:

-   -   Determining the copy number instability of the genome of a CRC         sample of said subject wherein said sample comprises at least         one colorectal cancer cell;     -   Administering anti-VEGF therapy to a subject, if said sample of         said subject is characterized by a high copy number instability,         wherein a high copy number instability means that 20% or more of         said genome is affected by copy number alterations, wherein said         genome comprises the genomic regions used for the analysis and         selected from Table 1 or Table 5 or Table 6 or Table 10.

In a more particular embodiment, the anti-VEGF therapy is bevacizumab therapy.

In another embodiment the invention provides a method of treating colorectal cancer in a subject in need thereof, comprising:

-   -   Determining the copy number instability of the genome of a CRC         sample of said subject wherein said sample comprises at least         one colorectal cancer cell;     -   Administering anti-VEGF therapy to a subject, if said sample of         said subject is characterized by a high copy number instability,         wherein a high copy number instability means that 26% or more of         said genome is affected by copy number alterations, wherein said         genome comprises the genomic regions used for the analysis and         selected from Table 1 or Table 5 or Table 6 or Table 10.

In a more particular embodiment, the anti-VEGF therapy is bevacizumab therapy.

In another embodiment the invention provides a method of treating colorectal cancer in a subject in need thereof, comprising:

-   -   Determining the copy number instability of a CRC sample of said         subject using one of the biomarker panels disclosed in the first         aspect of the application or using a biomarker panel comprising         at least 5 genomic regions or fragments thereof selected from         Table 1 or Table 5 or Table 6 or Table 10;     -   Administering anti-VEGF therapy to said subject, if 15% or more         of said CRC sample of said subject is affected by copy number         alterations.

In a more particular embodiment, the anti-VEGF therapy is bevacizumab therapy.

In another embodiment the invention provides a method of treating colorectal cancer in a subject in need thereof, comprising:

-   -   Determining the copy number instability of a CRC sample of said         subject using one of the biomarker panels disclosed in the first         aspect of the application or using a biomarker panel comprising         at least 6 genomic regions or fragments thereof selected from         Table 1 or Table 5 or Table 6 or Table 10;     -   Administering anti-VEGF therapy to a said subject, if 20% or         more of said CRC sample of said subject is affected by copy         number alterations.

In a more particular embodiment, the anti-VEGF therapy is bevacizumab therapy.

In another embodiment the invention provides a method of treating colorectal cancer in a subject in need thereof, comprising:

-   -   Determining the copy number instability of a CRC sample of said         subject using one of the biomarker panels disclosed in the first         aspect of the application or using a biomarker panel comprising         at least 6 genomic regions or fragments thereof selected from         Table 1 or Table 5 or Table 6 or Table 10;     -   Administering anti-VEGF therapy to said subject, if 26% or more         of said CRC sample of said subject is affected by copy number         alterations.

In a more particular embodiment, the anti-VEGF therapy is bevacizumab therapy.

In another embodiment the invention provides a kit to determine the copy number alteration status in a colorectal cancer sample, comprising primers or probes for detection of at least 5 genomic DNA regions or fragments thereof selected from Table 1, Table 5, Table 6 or Table 10. In another embodiment the invention provides a kit to determine the copy number instability of a colorectal cancer sample, comprising primers or probes for detection of at least 5 genomic DNA regions selected from Table 1, Table 5, Table 6 or Table 10.

It is to be understood that although particular embodiments, specific configurations as well as materials and/or molecules, have been discussed herein for cells and methods according to the present invention, various changes or modifications in form and detail may be made without departing from the scope and spirit of this invention. The following examples are provided to better illustrate particular embodiments, and they should not be considered limiting the application. The application is limited only by the claims.

EXAMPLES Example 1: Study Population

We collected tumor biopsies from 278 metastatic colorectal cancer (mCRC) patients. After confirming the histopathology and assessing tumor content as described in the methods, we successfully performed whole-exome sequencing (WES) on paired biopsies from 194 patients (Coverage 57.3±41.6×). Low-coverage whole-genome sequencing was performed on 238 patients and copy number profiles were generated as described in the methods section. Subsequently, we manually assessed each profile to check whether tumor content was sufficiently high resulting in 176 profiles that were used for further downstream analysis. In total 157 patients were treated with combination-bevacizumab (bvz) therapy, 2 with monotherapy bvz and 15 with chemotherapy backbone only. For the survival analyses, we excluded the 2 patients with mono-therapy for the survival analyses and furthermore excluded 16 patients that received combination-bvz therapy in 2nd, 3rd or 4th line (n=13, 2 and 1 respectively) for which no information about first-line therapy was available. Another 2 patients were excluded since no clinical information about the therapy was available. Furthermore we performed whole-exome sequencing on 128 out of the 156 patients. Additionally we downloaded publicly available copy number data of a cohort of 205 patients from the CAIRO trial that were treated with Irinotecan-Capecitabine (CAPIRI) or capecitabine (CAP) only (Agilent oligonucleotide hybridization arrays; GSE36864) (Haan et al 2014) and a cohort of 499 patients from the TCGA network (http://gdac.broadinstitute.org/). Furthermore, a second cohort 106 of combination bevacizumab treated metastatic colorectal tumors and accompanying normal tissue from the MOMA clinical trial was provided by The University of Pisa in Italy (NCT02271464). For this replication cohort, the same procedure was followed, resulting in 78 patients selected for further analysis. All patients were treated with combination-bvz therapy.

Example 2: Unsupervised Consensus Clustering of Copy Number Profiling Reveals 3 Clusters

GISTIC analysis was performed on all 880 tumors to identify the most frequent and overrepresented somatic copy number aberrations (SCNAs) in the tumors (hereafter referred to as recurrent SCNAs). This analysis revealed the presence of 43 recurrent focal amplifications and 59 recurrent focal deletions as well as whole-arm aberrations in every chromosome (Table 1; FIG. 1). We then performed unsupervised hierarchical clustering in an iterative manner using the status of each of the 102 regions and 78 whole-arms, resulting in 3 clusters to which patients could be assigned (FIG. 2; Table 2). Table 2 shows the specifications of a cluster 1 sample. The specifications of a CRC sample that is categorized in cluster 2 are shown in Table 3. The specifications which should be fulfilled by a CRC sample that is characterized as a cluster 3 sample are shown in Table 4.

Characterisation of the clusters on the somatic mutation and copy number level revealed that patients in clusters 2 and 3 had substantially more chromosomal breakpoints and a higher proportion of the genome was affected by copy number aberrations, while cluster 1 showed almost no CNAs or breakpoints (FIG. 2). We then focused on the somatic mutations that were detected using whole-exome sequencing (WES) for the 142 patients for which WES data was available and mutational data available for the TCGA samples. Cluster 1 was enriched for MSI-tumors (P=8.8×10⁻⁵⁷) and tumors with POLE and POLD1 mutations (P=4.8×10⁻⁰⁷), which are related to a hypermutator phenotype (P=1×10⁻²²) but also for BRAF (P=9.8×10⁻⁰⁵) and PIK3CA (P=5.5×10⁻¹¹) mutations. TP53 mutations were predominantly present in clusters 2 and 3 (P=4.4×10⁻⁰⁷), while APC and KRAS were evenly distributed among all 3 clusters. Cluster 1 showed a very high mutation rate confirming that this cluster is enriched for hypermutators, which is in line with the increased rate of POLE, POLD1 mutations and increased MSI tumors (FIG. 2).

Next, we performed Kaplan-Meier analysis to determine the relationship between the different clusters and the patients' progression free survival and overall survival. Univariate COX-regression revealed that cluster 3 correlated with slightly worse overall survival compared to cluster 1 (P=0.3×10⁻²; H R=1.44 CI95=1.03-1.99). However, multivariate analysis using a COX-regression with age, TNM-staging as numerical factors and age as categorical factor showed that not the cluster but primary tumor, regional lymph nodes and distant metastases staging are the main contributors to worse prognosis (P=2.53×10⁻⁴, HR=1.51, CI95=1.21-1.89; P=2.25×10⁻⁵, HR=1.35, CI95=1.17-1.55 and P=7.63×10⁻¹⁰, HR=2.36, CI95=1.80-3.11 respectively) (FIG. 3). Characterizing of the clusters on a clinical level revealed that clusters 2 and 3 were enriched for tumors with higher regional lymph nodes (P=3.4×10⁻⁷) and distant metastases staging (3.2×10⁻⁹) and higher stage numbers (P=1.5×10⁻¹²) (FIG. 4).

Example 3: Unsupervised Consensus Clustering of Metastatic Colorectal Cancer Patients

In a next step, we selected all the stage IV tumors, repeated the hierarchical clustering and performed the same characterization on clinical and genomic level. Similar as for all the colorectal samples, the subset of mCRC tumors showed an enrichment for TP53 mutations (P=5.2×10⁻⁴) and a substantially increased number of CNAs and breakpoints in clusters 2 and 3, while cluster 1 showed almost no CNAs and was enriched for MSI-tumors (P=2.1×10⁻¹⁵) and hypermutator phenotypes (P=1×10⁻⁵) as well as BRAF (P=2.6×10⁻³) and PIK3CA mutations (P=4.2×10³)(FIG. 5).

However, when assessing progression free and overall survival it became apparent that, compared to cluster 1, cluster 2 and 3 showed significantly better PFS (P=2.63×10⁻⁵, HR=0.44, CI95=0.30-0.65 and P=1.85×10⁻⁴, HR=0.50, CI95=0.34-0.72 for cluster 2 and 3 respectively) and OS (P=3.85×10⁻⁴, HR=0.48, CI95=0.32-0.72 and P=9.73×10⁻³, HR=0.60, CI95=0.41-0.88 for cluster 2 and 3 respectively). Multi-variate analysis correcting for relevant covariates confirmed that clusters 2 and 3 were significantly correlated with improved PFS (P=1.22×10⁻⁴, HR=0.45, CI95=0.30-0.68 and P=7.47×10⁻⁴, HR=0.52, CI95=0.35-0.76 for cluster 2 and 3 respectively) and OS (P=1.73×10³, HR=0.51, CI95=0.33-0.78 and P=1.92×10⁻², HR=0.62, CI95=0.41-0.92 for cluster 2 and 3 respectively), while primary tumor (P=2.35×10⁻², HR=1.27, CI95=1.03-1.57 and P=2.82×10⁻³, HR=1.42, CI95=1.13-1.78 for clusters 2 and 3) and regional lymph node staging contributed negatively (P=2.50×10⁻¹, HR=1.08, CI95=0.95-1.24 and P=1.09×10⁻², HR=1.21, CI95=1.04-1.39 for clusters 2 and 3)(FIG. 6). Characterization on a clinical level revealed no enrichments for particular clinical stages. (FIG. 7)

Example 4: Patients from Clusters 2 and 3 Show Additional Benefit from Combination-Avastin Therapy Compared to Patients Treated with Chemotherapy Only

We stratified patients in two groups, namely those that received combination-Avastin therapy (n=141) and a control group receiving combination chemotherapy only (n=220). For each cluster we used the Kaplan Meier method with a log-rank test to evaluate the correlation with progression-free survival and overall survival. For progression free survival, patients from clusters 2 and 3 showed a significant benefit when comparing patients treated with Avastin to the control group (P=3.23×10⁻³, HR=0.58, CI95=0.41-0.83 and P=2.01×10⁻⁶, HR=0.495, CI=0.37-66 for cluster 2 and 3 respectively). No difference was noted for the patients in cluster 1. Similar results were obtained when combining the patients from clusters 2 and 3 in one group (P=1.36×10⁻⁷, HR=0.54, CI95=0.43-0.68) (FIG. 8). Furthermore, multivariate analysis using COX-regression correcting for relevant covariables confirmed that clusters 2 and 3 were significantly correlated with improved PFS and OS for patients treated with Avastin compared to patients treated with standard-of-care therapy. Similar results were obtained for overall survival (FIG. 9).

Example 5: Relation Copy Number Instability (CIN) and Response to Avastin

Since patients from clusters 2 and 3 showed a good response to Avastin and these clusters were characterized by a higher CIN we hypothesized that tumors with CIN would have a better response to Avastin. We therefore divided the patients in two groups based on the proportion of the regions that are affected by CNAs (i.e. CNA-high tumors which have more affected regions the first quartile limit and CNA-low tumors with less than or equal to the first quartile limit)(Guinney et al 2015 Nature Medicine 21:1350-1356). When comparing CNA-high with CNA-low tumors within the group of patients that were treated with Avastin, CNA-high tumors showed a significant better progression free survival (P=1.74×10³; HR=0.513; CI95=0.30-0.88). Multivariate analysis using a COX-regression with age, TNM-staging as numerical factors and age as categorical factor revealed that this effect was also observed independent from clinical factors (P=3.4×10⁻³; HR=0.484; CI95=0.30-0.79). In contrast, this correlation was not observed when comparing CNA-high and CNA-low tumors in the control group (FIG. 10). Additionally we compared CNA-high tumors treated with Avastin to those that were not treated with Avastin. We observed a very strong association with increased survival for CNA-high patients treated with Avastin (P=3.1×10-9; HR=0.484; CI95=0.38-0.61). This correlation was confirmed using multivariate analysis (P=4.4×10-7; HR=0.497; CI95=0.38-0.65), again this correlation was observed independent from clinical factors. No such correlation was observed when assessing CNA-low patients treated with Avastin versus CNA-low patients not treated with Avastin (FIG. 10). Similar results were obtained when analysing overall survival.

Example 6: Hierarchical Clustering Using Only Focal Amplifications

To determine whether our clustering technique could also be performed using only focal CNAs we repeated the clustering using only focal CNAs as input (Table 5). This resulted in the identification of 3 very similar clusters. Characteristics of the three clusters when performing clustering on all CRC samples (n=883) are nearly identical to the clusters created with all 180 CNAs (FIG. 11). Similarly, in mCRC samples, cluster 1 is correlated with a worse prognosis compared to cluster 2 and 3 (FIG. 12) and clusters 2 and 3 are furthermore predictive for a beneficial response to bevacizumab (FIG. 13, 14).

Example 7: Methods for Single Sample Classification

In order to be able to classify a single sample to one of the three clusters and evaluate how many genomic regions are needed to classify a given CRC sample into one of the three predefined clusters we used 3 different techniques: recursive partitioning, random forest classification and k-nearest neighbour classification (Breiman et al 1984 Classification and regression trees, Wadsworth 368; Breiman 2001 Random Forest, Machine Learning 45:5-32; Venables and Ripley 2002 Modern Applied Statistics with S, Springer).

Recursive partitioning revealed that as little as 5 regions can be used to classify samples in one of the three defined clusters with an accuracy as high as 90.7% (FIG. 15). At first instance, we performed this analysis on all 180 regions. We were able to identify 36 regions that yielded the highest accuracy (Table 6; tier 1; average accuracy 89.1+−0.8% for 2789 generated trees using 5-11 regions per tree), a second set of 48 regions (Table 7; tier 2; n=5073 trees generated using 6-12 regions per tree) allowed to assign samples to the predefined clusters with an average accuracy of 87.0±0.9%, a third and fourth set of respectively 51 and 45 regions allowed to assign samples with an average accuracy of respectively 76.0±1.6% and 63.5±1.4% (Table 8 and 9; tier 3 and 4; n=7597 and 3555 trees using 5-16 and 4-13 regions per tree respectively). Similarly, using only the 102 regions that are affected by focal CNAs we were able to identify 33 regions that on average yielded the highest accuracy (Table 10; tier 1; 88.6±0.8% for 2378 generated trees using 5-13 regions per tree), a second set of 42 regions (Table 11; tier 2; n=3726 trees generated using 5-13 regions per tree) allowed to assign samples to the predefined clusters with an average accuracy of 85.4±1.3% and a third set of 27 regions allowed to assign samples with an average accuracy of 64.4±1.9% (Table 12; tier 3; n=9142 trees using 2-17 regions per tree).

In a second approach, we used the random forest classification algorithm to build a classification model using the predefined clusters from the hierarchical clustering as golden standard. In a first step, we performed a 10-fold cross-validation on the original dataset to determine the accuracy of the model. Hereto, we divided the 442 mCRC samples used for the original clustering 10 times at random, each time in a training set (90% of the samples) and validation set (10% of the samples) in such a manner that each sample is presented only once in the whole of 10 validation sets. Next a random forest classifier was generated from 500 balanced bootstraps of the training data. When we applied this classifier to the validation data the classifier demonstrated robust performance with high overall accuracy (94.1% and 91.5% for all 180 regions and only the 102 focal regions respectively) with a >90% balanced accuracy across all 3 clusters (Table 17). In a last step, we built a final model using the complete dataset as input and subsequently also calculated the contribution of each region to the final model. These contributions are represented in Table 13. Similarly, for the analysis using the 102 regions affected by focal CNAs only, the contribution of each region to this model is represented in Table 14.

It is of interest to note that the tier 1 and 2 from the recursive partitioning are also the highest ranking regions when comparing them with the random test contribution (Table 15 and table 16).

In a third approach, we used the k-nearest neighbors algorithm to build a classification model. Similar as the random forest classification we used a 10-fold cross validation to determine the model accuracy which was 86.6% and 87.3% for all 180 regions and only the 102 focal regions respectively with a >88% balanced accuracy across all 3 clusters. In a next step we applied these models to an independent dataset.

Example 8. Replication on an Independent Dataset Using Knn and Randomforest Classification

We applied both the k-nearest neighbors and random forest models to the additional dataset of 78 mCRC samples. Using both the k-nearest neighbouring model and the random forest classification we were able to classify the samples in 3 different clusters with very similar characteristics as the predefined clusters that arose from the hierarchical clustering. Further survival analysis again showed that patients from cluster 1 have worse PFS compared to patients from clusters 2 and 3 both in the analysis with all 180 regions as well as using only the 102 regions affected by focal CNAs (FIGS. 16 and 17 respectively).

Example 9. The Relation of Copy Number Instability in the Different Subsets of Regions and the Response to Avastin

Similar as in example 5 we divided the patients in two groups based on the proportion of the regions that are affected by CNAs (i.e. CNA-high tumors which have more affected regions the first quartile limit and CNA-low tumors with less than or equal to the first quartile limit) and performed this for 6 different subsets (1) using only the 102 focal regions, (2) using the top 50 ranked regions from the random forest classification model built with the 102 focal regions, (3) using the tier 1 and tier 2 regions from the recursive partitioning applied on the 102 focal regions, (4) using all 180 genomic regions (5) using the tier 1 and tier 2 regions from the recursive partitioning applied all 180 regions and (6) using the top 50 ranked regions from the random forest classification model built with the 102 focal regions (FIGS. 18-22, Table 18). For each of the subsets we observed that CNA-high tumors of patients treated with Avastin show a significant increase in progression free and overall survival compared to patients treated with standard-of-care chemotherapy. No such effect was noted for CNA-low tumors.

Example 10. Replication of the Relation Between CIN and Response to Avastin

Similar as the analysis in example 5 we stratified patients in CNA-high and CNA-low (with the thresholds set to 30% and 25% for the top 50 ranking regions from the random forest classifiers and the tier 1 and 2 regions for both only focal regions and all 180 regions respectively. For each of the different subsets of genomic regions CNA-high tumors showed an increased progression free survival (FIG. 23).

TABLE 1 Biomarker panel listing the 180 genomic regions used to cluster the studied CRC samples in 3 genomic subtypes. The panel of genomic regions consists of 43 focal amplifications, 59 focal deletions, 39 whole-arm amplifications and 39 whole-arm deletions. Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits Amplification 1p34.2 chr1: 39144054-44367347 chr1: 42834925-43114106 chr1: 42692914-43456374 Peak 1 (probes 8327:9928) (probes 9441:9533) (probes 9397:9635) Amplification 1q22 chr1: 120494739-199253746 chr1: 155143717-155177826 chr1: 120497533-175439985 Peak 2 (probes 33660:51419) (probes 35410:35412) (probes 33661:42337) Amplification 1q43 chr1: 201615295-249250621 chr1: 242413158-242638099 chr1: 242270003-249250621 Peak 3 (probes 52203:66664) (probes 65295:65368) (probes 65251:66664) Amplification 2q33.1 chr2: 181446594-243199373 chr2: 199603526-199649638 chr2: 199525178-199824262 Peak 4 (probes 121383:140439) (probes 127082:127089) (probes 127052:127139) Amplification 3q29 chr3: 174745992-198022430 chr3: 195922177-195991311 chr3: 174746836-198022430 Peak 5 (probes 195590:202834) (probes 202552:202570) (probes 195591:202834) Amplification 5p15.33 chr5: 1-6418038 chr5: 1-949725 chr5: 1-2807521 Peak 6 (probes 260156:261588) (probes 260156:260170) (probes 260156:260460) Amplification 5p12 chr5: 33430780-50470114 chr5: 43822799-43929095 chr5: 37334807-44266311 Peak 7 (probes 269602:272992) (probes 272538:272572) (probes 270584:272613) Amplification 6p21.1 chr6: 43545080-44164949 chr6: 43765716-44163738 chr6: 36748055-52028937 Peak 8 (probes 323466:323553) (probes 323497:323552) (probes 321584:325929) Amplification 6q23.3 chr6: 135342981-135632150 chr6: 135513416-135593890 chr6: 133418393-138096856 Peak 9 (probes 350621:350776) (probes 350670:350763) (probes 350049:351529) Amplification 7p11.2 chr7: 54949302-55950640 chr7: 55248172-55271747 chr7: 54949902-55955413 Peak 10 (probes 380333:380688) (probes 380546:380547) (probes 380334:380690) Amplification 8p11.23 chr8: 38162916-38237532 chr8: 38165117-38236937 chr8: 34342520-48854434 Peak 11 (probes 417907:417912) (probes 417908:417911) (probes 417738:418611) Amplification 8p11.21 chr8: 41760295-42054539 chr8: 41767516-41796226 chr8: 34342520-48854434 Peak 12 (probes 418156:418183) (probes 418157:418159) (probes 417738:418611) Amplification 8q12.2 chr8: 60847395-62906825 chr8: 61658252-61874896 chr8: 54646329-146364022 Peak 13 (probes 421733:422344) (probes 421947:422037) (probes 420141:444693) Amplification 8q21.13 chr8: 80636493-82552412 chr8: 81853752-81935079 chr8: 54646329-146364022 Peak 14 (probes 427272:427752) (probes 427579:427595) (probes 420141:444693) Amplification 8q22.3 chr8: 101853171-101878037 chr8: 101853464-101876083 chr8: 54646329-146364022 Peak 15 (probes 432850:432855) (probes 432851:432854) (probes 420141:444693) Amplification 8q24.21 chr8: 128574277-128592142 chr8: 128574768-128591041 chr8: 54646329-146364022 Peak 16 (probes 440457:440461) (probes 440458:440460) (probes 420141:444693) Amplification 10q22.3 chr10: 79956009-83248579 chr10: 80445049-80732930 chr10: 77952482-83583616 Peak 17 (probes 504622:505397) (probes 504807:504859) (probes 503919:505484) Amplification 11p15.5 chr11: 2091739-2302637 chr11: 2095340-2301396 chr11: 2095340-2305324 Peak 18 (probes 520960:520971) (probes 520961:520970) (probes 520961:520973) Amplification 11q13.3 chr11: 68746750-69827851 chr11: 69311828-69824706 chr11: 68748468-70760456 Peak 19 (probes 539709:539869) (probes 539796:539868) (probes 539710:540034) Amplification 12p13.32 chr12: 3941807-4552801 chr12: 4257035-4414967 chr12: 1-8970181 Peak 20 (probes 562075:562238) (probes 562162:562219) (probes 561076:563266) Amplification 12p11.22 chr12: 24880798-28477058 chr12: 27800441-27813180 chr12: 25955987-28156868 Peak 21 (probes 567897:568917) (probes 568722:568722) (probes 568181:568838) Amplification 13q12.2 chr13: 28164386-28564331 chr13: 28174614-28222659 chr13: 1-115169878 Peak 22 (probes 600542:600653) (probes 600543:600550) (probes 599000:624834) Amplification 13q22.1 chr13: 73775176-74007122 chr13: 73906681-74004816 chr13: 1-115169878 Peak 23 (probes 612853:612922) (probes 612891:612921) (probes 599000:624834) Amplification 13q34 chr13: 110097815-111753132 chr13: 110614601-110852082 chr13: 1-115169878 Peak 24 (probes 624037:624356) (probes 624207:624235) (probes 599000:624834) Amplification 15q26.1 chr15: 84648780-102531392 chr15: 90811423-90958538 chr15: 90086447-91895585 Peak 25 (probes 669559:675028) (probes 671504:671507) (probes 671145:671795) Amplification 16p11.2 chr16: 30548665-30684980 chr16: 30549334-30682578 chr16: 28556705-46663588 Peak 26 (probes 681497:681499) (probes 681498:681498) (probes 681456:681707) Amplification 16q12.1 chr16: 52243935-52652774 chr16: 52383686-52652198 chr16: 51078632-53117566 Peak 27 (probes 683896:684007) (probes 683905:684006) (probes 683397:684118) Amplification 17q11.2 chr17: 27339261-27528113 chr17: 27339592-27419750 chr17: 20042949-40168023 Peak 28 (probes 701849:701907) (probes 701850:701866) (probes 701549:704344) Amplification 17q12 chr17: 37747533-38052599 chr17: 37950674-38031986 chr17: 20042949-40168023 Peak 29 (probes 703891:703930) (probes 703917:703929) (probes 701549:704344) Amplification 17q23.2 chr17: 58400463-58674819 chr17: 58400997-58532661 chr17: 57045336-62714320 Peak 30 (probes 708991:709072) (probes 708992:709031) (probes 708646:710280) Amplification 17q24.2 chr17: 65638523-65873408 chr17: 65649475-65769071 chr17: 63042470-68655121 Peak 31 (probes 710976:711074) (probes 710978:711037) (probes 710378:712109) Amplification 17q25.3 chr17: 77601682-77857881 chr17: 77766436-77856811 chr17: 75845339-81195210 Peak 32 (probes 714127:714155) (probes 714137:714154) (probes 713778:714413) Amplification 18q11.2 chr18: 19517253-20155059 chr18: 19525020-20154578 chr18: 19243919-21268418 Peak 33 (probes 718275:718278) (probes 718276:718277) (probes 718239:718447) Amplification 18q21.1 chr18: 46041609-46930382 chr18: 46474762-46604295 chr18: 46043163-46624631 Peak 34 (probes 725325:725688) (probes 725462:725478) (probes 725326:725481) Amplification 19q13.11 chr19: 32439834-33021877 chr19: 32966965-32988344 chr19: 19939350-41312227 Peak 35 (probes 739770:739825) (probes 739799:739805) (probes 739769:742785) Amplification 19q13.2 chr19: 39844313-40357920 chr19: 39848086-40009185 chr19: 19939350-41312227 Peak 36 (probes 742339:742488) (probes 742340:742365) (probes 739769:742785) Amplification 20p12.3 chr20: 5376354-5742957 chr20: 5379141-5737687 chr20: 5156552-5961498 Peak 37 (probes 749386:749394) (probes 749387:749393) (probes 749320:749400) Amplification 20p12.1 chr20: 16140291-16967195 chr20: 16488303-16962609 chr20: 16146669-16970141 Peak 38 (probes 751931:752121) (probes 751982:752120) (probes 751932:752123) Amplification 20p11.22 chr20: 22058560-22353663 chr20: 22063756-22350551 chr20: 20938975-24286806 Peak 39 (probes 753204:753212) (probes 753205:753211) (probes 753103:753480) Amplification 20q11.21 chr20: 29981165-30284236 chr20: 30158807-30231055 chr20: 24375411-63025520 Peak 40 (probes 753711:753769) (probes 753729:753748) (probes 753519:762719) Amplification 20q13.12 chr20: 42534268-43281676 chr20: 42537604-42773258 chr20: 24375411-63025520 Peak 41 (probes 756743:756930) (probes 756744:756753) (probes 753519:762719) Amplification 20q13.2 chr20: 52240629-52852159 chr20: 52246659-52447690 chr20: 24375411-63025520 Peak 42 (probes 759885:759989) (probes 759886:759947) (probes 753519:762719) Amplification 20q13.32 chr20: 56110288-57258354 chr20: 57000076-57085518 chr20: 24375411-63025520 Peak 43 (probes 760955:761384) (probes 761307:761325) (probes 753519:762719) Deletion Peak 1 1p36.31 chr1: 4843384-6053964 chr1: 5646446-6050774 chr1: 1-37080378 (probes 343:539) (probes 537:538) (probes 1:7694) Deletion Peak 2 1p36.11 chr1: 26898389-27219375 chr1: 27139248-27185402 chr1: 1-37080378 (probes 5577:5639) (probes 5629:5630) (probes 1:7694) Deletion Peak 3 1p33 chr1: 49187432-50544677 chr1: 48847112-50490440 chr1: 49196205-51396500 (probes 11383:11605) (probes 11319:11598) (probes 11385:11801) Deletion Peak 4 1p31.1 chr1: 68959091-82269682 chr1: 79308665-79566142 chr1: 54944113-149961894 (probes 17617:22019) (probes 20993:20994) (probes 12746:33663) Deletion Peak 5 1p21.1 chr1: 102460262-107618224 chr1: 104041213-104355050 chr1: 54944113-149961894 (probes 28724:30035) (probes 29059:29060) (probes 12746:33663) Deletion Peak 6 2p25.3 chr2: 1-4752017 chr2: 1-488785 chr2: 1-5260278 (probes 66665:67509) (probes 66665:66665) (probes 66665:67543) Deletion Peak 7 2p21 chr2: 42587649-44009118 chr2: 43440855-43455807 chr2: 43159857-43470966 (probes 79800:80265) (probes 80094:80097) (probes 79991:80104) Deletion Peak 8 2q23.1 chr2: 147341956-149499455 chr2: 148437688-148750846 chr2: 148444810-148756213 (probes 110935:111344) (probes 111211:111212) (probes 111212:111213) Deletion Peak 9 2q37.3 chr2: 240321205-243199373 chr2: 240940975-241060875 chr2: 240589192-241997730 (probes 139897:140439) (probes 140116:140117) (probes 139997:140352) Deletion Peak 3p26.3 chr3: 1-8350135 chr3: 1-2251569 chr3: 1-9456413 10 (probes 140440:142376) (probes 140440:140440) (probes 140440:142660) Deletion Peak 3p14.2 chr3: 58946448-61555632 chr3: 59692189-61457375 chr3: 59692189-61460946 11 (probes 159123:159363) (probes 159317:159339) (probes 159317:159341) Deletion Peak 3p13 chr3: 70014100-71250049 chr3: 70976616-71182883 chr3: 70977475-71315576 12 (probes 162276:162774) (probes 162708:162756) (probes 162709:162793) Deletion Peak 3q26.31 chr3: 173995229-175766885 chr3: 174575326-175766885 chr3: 174646449-174998725 13 (probes 195434:195620) (probes 195555:195620) (probes 195574:195593) Deletion Peak 4p16.2 chr4: 1-9787265 chr4: 5915497-5925651 chr4: 1-11455571 14 (probes 202835:205184) (probes 204117:204118) (probes 202835:205810) Deletion Peak 4q22.1 chr4: 91143530-93226628 chr4: 91046982-92557520 chr4: 91103554-92561908 15 (probes 229840:230295) (probes 229814:230049) (probes 229834:230051) Deletion Peak 4q25 chr4: 109046573-109544048 chr4: 109451604-109544048 chr4: 109489936-109535239 16 (probes 235677:235829) (probes 235801:235829) (probes 235811:235826) Deletion Peak 4q31.3 chr4: 152679194-153694102 chr4: 153232273-153473069 chr4: 152233433-191154276 17 (probes 249686:250016) (probes 249909:249977) (probes 249594:260155) Deletion Peak 4q32.1 chr4: 156135292-162306004 chr4: 159683040-159830757 chr4: 152233433-191154276 18 (probes 250770:252941) (probes 252055:252100) (probes 249594:260155) Deletion Peak 4q35.1 chr4: 184432080-185262191 chr4: 184545375-185154488 chr4: 152233433-191154276 19 (probes 259152:259216) (probes 259180:259181) (probes 249594:260155) Deletion Peak 5p15.33 chr5: 1-2750686 chr5: 1368344-2252637 chr5: 1-3864653 20 (probes 260156:260443) (probes 260268:260279) (probes 260156:260838) Deletion Peak 5q12.1 chr5: 58263825-59784640 chr5: 58263825-59784640 chr5: 50968806-135478060 21 (probes 275334:275642) (probes 275334:275642) (probes 273162:297537) Deletion Peak 5q22.2 chr5: 111312546-112362638 chr5: 111747052-111761475 chr5: 50968806-135478060 22 (probes 290226:290685) (probes 290365:290367) (probes 273162:297537) Deletion Peak 6p25.3 chr6: 1613114-2256643 chr6: 1621843-2256643 chr6: 1626114-2752758 23 (probes 311779:311876) (probes 311784:311876) (probes 311786:312043) Deletion Peak 6p22.2 chr6: 25926929-26025173 chr6: 25932794-26025173 chr6: 25933563-26346501 24 (probes 319619:319631) (probes 319620:319631) (probes 319621:319690) Deletion Peak 6q21 chr6: 91006553-129206367 chr6: 111544567-112706964 chr6: 108785353-116683959 25 (probes 337170:348684) (probes 343210:343577) (probes 342315:344882) Deletion Peak 6q26 chr6: 161540781-163179430 chr6: 161540781-163179430 chr6: 160448048-171115067 26 (probes 359016:359155) (probes 359016:359155) (probes 358753:361110) Deletion Peak 7q31.1 chr7: 109590674-111367757 chr7: 110232248-111358792 chr7: 110595801-110618403 27 (probes 392698:393070) (probes 392932:393069) (probes 393001:393002) Deletion Peak 8p23.3 chr8: 1-1449850 chr8: 1-623109 chr8: 1-10801317 28 (probes 408036:408314) (probes 408036:408036) (probes 408036:410838) Deletion Peak 8p21.3 chr8: 13423967-26607015 chr8: 21547484-21647267 chr8: 11646511-25738962 29 (probes 411497:416107) (probes 414395:414425) (probes 411142:415781) Deletion Peak 8p12 chr8: 33445578-37452445 chr8: 34944675-36494184 chr8: 35186331-35207233 30 (probes 417581:417886) (probes 417838:417861) (probes 417850:417851) Deletion Peak 8q11.1 chr8: 42874387-48101823 chr8: 42931769-48061147 chr8: 42932439-48062091 31 (probes 418403:418427) (probes 418413:418414) (probes 418414:418415) Deletion Peak 9p21.3 chr9: 21558582-22452906 chr9: 21995318-22021004 chr9: 21711940-22331169 32 (probes 452306:452602) (probes 452487:452491) (probes 452378:452557) Deletion Peak 10p15.3 chr10: 1-855610 chr10: 1-418075 chr10: 1-2055670 33 (probes 482107:482163) (probes 482107:482107) (probes 482107:482391) Deletion Peak 10q21.1 chr10: 51561927-53481136 chr10: 51561927-54065263 chr10: 50763189-54253314 34 (probes 495717:495904) (probes 495717:496053) (probes 495699:496079) Deletion Peak 10q23.31 chr10: 89502327-90051809 chr10: 89574482-89607380 chr10: 83248858-135534747 35 (probes 507191:507378) (probes 507201:507204) (probes 505400:520735) Deletion Peak 10q25.2 chr10: 114197471-115353755 chr10: 114708532-114929210 chr10: 83248858-135534747 36 (probes 515003:515382) (probes 515200:515269) (probes 505400:520735) Deletion Peak 10q26.3 chr10: 133107199-135534747 chr10: 135221096-135534747 chr10: 83248858-135534747 37 (probes 520190:520735) (probes 520735:520735) (probes 505400:520735) Deletion Peak 11q22.3 chr11: 102958343-135006516 chr11: 108251085-108350263 chr11: 108179920-108470348 38 (probes 551128:561075) (probes 552798:552832) (probes 552783:552882) Deletion Peak 12p13.2 chr12: 12412186-13039757 chr12: 12525464-12721981 chr12: 11739866-13828006 39 (probes 564161:564352) (probes 564230:564257) (probes 563986:564574) Deletion Peak 12q21.2 chr12: 75602135-79819184 chr12: 76423769-76523220 chr12: 75648890-78593389 40 (probes 581594:583083) (probes 581862:581874) (probes 581614:582689) Deletion Peak 12q24.33 chr12: 125048064-133851895 chr12: 131256822-131362341 chr12: 125246979-133851895 41 (probes 597584:598999) (probes 598784:598790) (probes 597646:598999) Deletion Peak 14q24.1 chr14: 68280014-69351476 chr14: 68284712-68948164 chr14: 68343659-68985929 42 (probes 640423:640650) (probes 640425:640565) (probes 640446:640573) Deletion Peak 14q32.11 chr14: 78347564-107349540 chr14: 90999841-91286309 chr14: 90170502-92315681 43 (probes 643482:652331) (probes 647605:647693) (probes 647318:648035) Deletion Peak 15q11.2 chr15: 25436434-25466900 chr15: 25438412-25459423 chr15: 1-58781038 44 (probes 652975:652987) (probes 652978:652984) (probes 652332:661726) Deletion Peak 15q21.1 chr15: 44850582-45321541 chr15: 44851811-45052539 chr15: 1-58781038 45 (probes 657156:657216) (probes 657157:657198) (probes 652332:661726) Deletion Peak 15q22.33 chr15: 67053712-67697647 chr15: 67337017-67551787 chr15: 67245914-67753643 46 (probes 664346:664503) (probes 664432:664448) (probes 664397:664514) Deletion Peak 16p13.3 chr16: 5141600-8053542 chr16: 6056420-8053542 chr16: 5279421-7736962 47 (probes 676035:676388) (probes 676266:676388) (probes 676069:676383) Deletion Peak 16q23.1 chr16: 78131135-79628242 chr16: 78131135-79286336 chr16: 78424695-79295468 48 (probes 692486:692917) (probes 692486:692739) (probes 692585:692741) Deletion Peak 17p12 chr17: 11466949-12461211 chr17: 11872374-11906034 chr17: 10231123-12752622 49 (probes 699252:699560) (probes 699350:699356) (probes 698870:699686) Deletion Peak 17q24.3 chr17: 68174484-70599305 chr17: 70337175-70590424 chr17: 70549664-70552757 50 (probes 711906:712713) (probes 712684:712712) (probes 712699:712700) Deletion Peak 18p11.31 chr18: 3277394-4265401 chr18: 3441391-3481373 chr18: 3398771-3729936 51 (probes 715148:715497) (probes 715189:715190) (probes 715178:715261) Deletion Peak 18q12.2 chr18: 35136370-39061915 chr18: 36781295-37333625 chr18: 35827844-46846953 52 (probes 722194:723278) (probes 722627:722752) (probes 722377:725639) Deletion Peak 18q21.2 chr18: 48472034-48707815 chr18: 48547928-48660122 chr18: 47049746-78077248 53 (probes 725965:726002) (probes 725987:725988) (probes 725727:734875) Deletion Peak 18q21.33 chr18: 60645473-61013467 chr18: 60788090-61013467 chr18: 47049746-78077248 54 (probes 730126:730222) (probes 730167:730222) (probes 725727:734875) Deletion Peak 19p13.3 chr19: 1488247-1660256 chr19: 1488455-1660256 chr19: 1-5957502 55 (probes 735045:735049) (probes 735046:735049) (probes 734876:735790) Deletion Peak 20p12.1 chr20: 13955189-16350354 chr20: 14416445-15462745 chr20: 14096517-16064189 56 (probes 751741:751931) (probes 751773:751774) (probes 751766:751890) Deletion Peak 21q11.2 chr21: 15555708-16334057 chr21: 15854887-15919066 chr21: 1-31258004 57 (probes 762725:762981) (probes 762833:762869) (probes 762720:767383) Deletion Peak 21q21.1 chr21: 23106546-26219369 chr21: 23248652-23494410 chr21: 1-31258004 58 (probes 765049:765801) (probes 765109:765118) (probes 762720:767383) Deletion Peak 22q13.32 chr22: 48649199-49178363 chr22: 48906309-49158314 chr22: 47983027-51304566 59 (probes 781080:781144) (probes 781137:781140) (probes 780856:781177) Whole arm 10p NA NA chr10: 1-39254935 amplification 1 Whole arm 10q NA NA chr10: 42254935-135534747 amplification 2 Whole arm 11p NA NA chr11: 1-51644205 amplification 3 Whole arm 11q NA NA chr11: 54644205-135006516 amplification 4 Whole arm 12p NA NA chr12: 1-34856694 amplification 5 Whole arm 12q NA NA chr12: 37856694-133851895 amplification 6 Whole arm 13q NA NA chr13: 19000000-115169878 amplification 7 Whole arm 14q NA NA chr14: 19000000-107349540 amplification 8 Whole arm 15q NA NA chr15: 20000000-102531392 amplification 9 Whole arm 16p NA NA chr16: 1-35335801 amplification 10 Whole arm 16q NA NA chr16: 38335801-90354753 amplification 11 Whole arm 17p NA NA chr17: 1-22263006 amplification 12 Whole arm 17q NA NA chr17: 25263006-81195210 amplification 13 Whole arm 18p NA NA chr18: 1-15460898 amplification 14 Whole arm 18q NA NA chr18: 18460898-78077248 amplification 15 Whole arm 19p NA NA chr19: 1-24681782 amplification 16 Whole arm 19q NA NA chr19: 27681782-59128983 amplification 17 Whole arm 1p NA NA chr1: 1-121535434 amplification 18 Whole arm 1q NA NA chr1: 124535434-249250621 amplification 19 Whole arm 20p NA NA chr20: 1-26369569 amplification 20 Whole arm 20q NA NA chr20: 29369569-63025520 amplification 21 Whole arm 21q NA NA chr21: 14288129-48129895 amplification 22 Whole arm 22q NA NA chr22: 16000000-51304566 amplification 23 Whole arm 2p NA NA chr2: 1-92326171 amplification 24 Whole arm 2q NA NA chr2: 95326171-243199373 amplification 25 Whole arm 3p NA NA chr3: 1-90504854 amplification 26 Whole arm 3q NA NA chr3: 93504854-198022430 amplification 27 Whole arm 4p NA NA chr4: 1-49660117 amplification 28 Whole arm 4q NA NA chr4: 52660117-191154276 amplification 29 Whole arm 5p NA NA chr5: 1-46405641 amplification 30 Whole arm 5q NA NA chr5: 49405641-180915260 amplification 31 Whole arm 6p NA NA chr6: 1-58830166 amplification 32 Whole arm 6q NA NA chr6: 61830166-171115067 amplification 33 Whole arm 7p NA NA chr7: 1-58054331 amplification 34 Whole arm 7q NA NA chr7: 61054331-159138663 amplification 35 Whole arm 8p NA NA chr8: 1-43838887 amplification 36 Whole arm 8q NA NA chr8: 46838887-146364022 amplification 37 Whole arm 9p NA NA chr9: 1-47367679 amplification 38 Whole arm 9q NA NA chr9: 50367679-141213431 amplification 39 Whole arm 10p NA NA chr10: 1-39254935 deletion 1 Whole arm 10q NA NA chr10: 42254935-135534747 deletion 2 Whole arm 11p NA NA chr11: 1-51644205 deletion 3 Whole arm 11q NA NA chr11: 54644205-135006516 deletion 4 Whole arm 12p NA NA chr12: 1-34856694 deletion 5 Whole arm 12q NA NA chr12: 37856694-133851895 deletion 6 Whole arm 13q NA NA chr13: 19000000-115169878 deletion 7 Whole arm 14q NA NA chr14: 19000000-107349540 deletion 8 Whole arm 15q NA NA chr15: 20000000-102531392 deletion 9 Whole arm 16p NA NA chr16: 1-35335801 deletion 10 Whole arm 16q NA NA chr16: 38335801-90354753 deletion 11 Whole arm 17p NA NA chr17: 1-22263006 deletion 12 Whole arm 17q NA NA chr17: 25263006-81195210 deletion 13 Whole arm 18p NA NA chr18: 1-15460898 deletion 14 Whole arm 18q NA NA chr18: 18460898-78077248 deletion 15 Whole arm 19p NA NA chr19: 1-24681782 deletion 16 Whole arm 19q NA NA chr19: 27681782-59128983 deletion 17 Whole arm 1p NA NA chr1: 1-121535434 deletion 18 Whole arm 1q NA NA chr1: 124535434-249250621 deletion 19 Whole arm 20p NA NA chr20: 1-26369569 deletion 20 Whole arm 20q NA NA chr20: 29369569-63025520 deletion 21 Whole arm 21q NA NA chr21: 14288129-48129895 deletion 22 Whole arm 22q NA NA chr22: 16000000-51304566 deletion 23 Whole arm 2p NA NA chr2: 1-92326171 deletion 24 Whole arm 2q NA NA chr2: 95326171-243199373 deletion 25 Whole arm 3p NA NA chr3: 1-90504854 deletion 26 Whole arm 3q NA NA chr3: 93504854-198022430 deletion 27 Whole arm 4p NA NA chr4: 1-49660117 deletion 28 Whole arm 4q NA NA chr4: 52660117-191154276 deletion 29 Whole arm 5p NA NA chr5: 1-46405641 deletion 30 Whole arm 5q NA NA chr5: 49405641-180915260 deletion 31 Whole arm 6p NA NA chr6: 1-58830166 deletion 32 Whole arm 6q NA NA chr6: 61830166-171115067 deletion 33 Whole arm 7p NA NA chr7: 1-58054331 deletion 34 Whole arm 7q NA NA chr7: 61054331-159138663 deletion 35 Whole arm 8p NA NA chr8: 1-43838887 deletion 36 Whole arm 8q NA NA chr8: 46838887-146364022 deletion 37 Whole arm 9p NA NA chr9: 1-47367679 deletion 38 Whole arm 9q NA NA chr9: 50367679-141213431 deletion 39

TABLE 2 The copy number alteration specifications of cluster1 (genetic subtype 1). All genomic regions of the biomarker panel of Table 1 are listed together with the frequency that these regions are affected in cluster 1. Frequency of region being affected in Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits cluster 1 Amplification 1p34.2 chr1: 39144054-44367347 chr1: 42834925-43114106 chr1: 42692914-43456374 0.00 Peak 1 Amplification 1q22 chr1: 120494739-199253746 chr1: 155143717-155177826 chr1: 120497533-175439985 0.09 Peak 2 Amplification 1q43 chr1: 201615295-249250621 chr1: 242413158-242638099 chr1: 242270003-249250621 0.09 Peak 3 Amplification 2q33.1 chr2: 181446594-243199373 chr2: 199603526-199649638 chr2: 199525178-199824262 0.06 Peak 4 Amplification 3q29 chr3: 174745992-198022430 chr3: 195922177-195991311 chr3: 174746836-198022430 0.03 Peak 5 Amplification 5p15.33 chr5: 1-6418038 chr5: 1-949725 chr5: 1-2807521 0.03 Peak 6 Amplification 5p12 chr5: 33430780-50470114 chr5: 43822799-43929095 chr5: 37334807-44266311 0.00 Peak 7 Amplification 6p21.1 chr6: 43545080-44164949 chr6: 43765716-44163738 chr6: 36748055-52028937 0.06 Peak 8 Amplification 6q23.3 chr6: 135342981-135632150 chr6: 135513416-135593890 chr6: 133418393-138096856 0.09 Peak 9 Amplification 7p11.2 chr7: 54949302-55950640 chr7: 55248172-55271747 chr7: 54949902-55955413 0.34 Peak 10 Amplification 8p11.23 chr8: 38162916-38237532 chr8: 38165117-38236937 chr8: 34342520-48854434 0.17 Peak 11 Amplification 8p11.21 chr8: 41760295-42054539 chr8: 41767516-41796226 chr8: 34342520-48854434 0.17 Peak 12 Amplification 8q12.2 chr8: 60847395-62906825 chr8: 61658252-61874896 chr8: 54646329-146364022 0.23 Peak 13 Amplification 8q21.13 chr8: 80636493-82552412 chr8: 81853752-81935079 chr8: 54646329-146364022 0.23 Peak 14 Amplification 8q22.3 chr8: 101853171-101878037 chr8: 101853464-101876083 chr8: 54646329-146364022 0.26 Peak 15 Amplification 8q24.21 chr8: 128574277-128592142 chr8: 128574768-128591041 chr8: 54646329-146364022 0.29 Peak 16 Amplification 10q22.3 chr10: 79956009-83248579 chr10: 80445049-80732930 chr10: 77952482-83583616 0.03 Peak 17 Amplification 11p15.5 chr11: 2091739-2302637 chr11: 2095340-2301396 chr11: 2095340-2305324 0.00 Peak 18 Amplification 11q13.3 chr11: 68746750-69827851 chr11: 69311828-69824706 chr11: 68748468-70760456 0.00 Peak 19 Amplification 12p13.32 chr12: 3941807-4552801 chr12: 4257035-4414967 chr12: 1-8970181 0.20 Peak 20 Amplification 12p11.22 chr12: 24880798-28477058 chr12: 27800441-27813180 chr12: 25955987-28156868 0.17 Peak 21 Amplification 13q12.2 chr13: 28164386-28564331 chr13: 28174614-28222659 chr13: 1-115169878 0.14 Peak 22 Amplification 13q22.1 chr13: 73775176-74007122 chr13: 73906681-74004816 chr13: 1-115169878 0.11 Peak 23 Amplification 13q34 chr13: 110097815-111753132 chr13: 110614601-110852082 chr13: 1-115169878 0.17 Peak 24 Amplification 15q26.1 chr15: 84648780-102531392 chr15: 90811423-90958538 chr15: 90086447-91895585 0.00 Peak 25 Amplification 16p11.2 chr16: 30548665-30684980 chr16: 30549334-30682578 chr16: 28556705-46663588 0.11 Peak 26 Amplification 16q12.1 chr16: 52243935-52652774 chr16: 52383686-52652198 chr16: 51078632-53117566 0.03 Peak 27 Amplification 17q11.2 chr17: 27339261-27528113 chr17: 27339592-27419750 chr17: 20042949-40168023 0.03 Peak 28 Amplification 17q12 chr17: 37747533-38052599 chr17: 37950674-38031986 chr17: 20042949-40168023 0.00 Peak 29 Amplification 17q23.2 chr17: 58400463-58674819 chr17: 58400997-58532661 chr17: 57045336-62714320 0.11 Peak 30 Amplification 17q24.2 chr17: 65638523-65873408 chr17: 65649475-65769071 chr17: 63042470-68655121 0.09 Peak 31 Amplification 17q25.3 chr17: 77601682-77857881 chr17: 77766436-77856811 chr17: 75845339-81195210 0.09 Peak 32 Amplification 18q11.2 chr18: 19517253-20155059 chr18: 19525020-20154578 chr18: 19243919-21268418 0.11 Peak 33 Amplification 18q21.1 chr18: 46041609-46930382 chr18: 46474762-46604295 chr18: 46043163-46624631 0.09 Peak 34 Amplification 19q13.11 chr19: 32439834-33021877 chr19: 32966965-32988344 chr19: 19939350-41312227 0.17 Peak 35 Amplification 19q13.2 chr19: 39844313-40357920 chr19: 39848086-40009185 chr19: 19939350-41312227 0.23 Peak 36 Amplification 20p12.3 chr20: 5376354-5742957 chr20: 5379141-5737687 chr20: 5156552-5961498 0.00 Peak 37 Amplification 20p12.1 chr20: 16140291-16967195 chr20: 16488303-16962609 chr20: 16146669-16970141 0.00 Peak 38 Amplification 20p11.22 chr20: 22058560-22353663 chr20: 22063756-22350551 chr20: 20938975-24286806 0.00 Peak 39 Amplification 20q11.21 chr20: 29981165-30284236 chr20: 30158807-30231055 chr20: 24375411-63025520 0.00 Peak 40 Amplification 20q13.12 chr20: 42534268-43281676 chr20: 42537604-42773258 chr20: 24375411-63025520 0.00 Peak 41 Amplification 20q13.2 chr20: 52240629-52852159 chr20: 52246659-52447690 chr20: 24375411-63025520 0.00 Peak 42 Amplification 20q13.32 chr20: 56110288-57258354 chr20: 57000076-57085518 chr20: 24375411-63025520 0.00 Peak 43 Deletion Peak 1 1p36.31 chr1: 4843384-6053964 chr1: 5646446-6050774 chr1: 1-37080378 0.14 Deletion Peak 2 1p36.11 chr1: 26898389-27219375 chr1: 27139248-27185402 chr1: 1-37080378 0.14 Deletion Peak 3 1p33 chr1: 49187432-50544677 chr1: 48847112-50490440 chr1: 49196205-51396500 0.03 Deletion Peak 4 1p31.1 chr1: 68959091-82269682 chr1: 79308665-79566142 chr1: 54944113-149961894 0.03 Deletion Peak 5 1p21.1 chr1: 102460262-107618224 chr1: 104041213-104355050 chr1: 54944113-149961894 0.03 Deletion Peak 6 2p25.3 chr2: 1-4752017 chr2: 1-488785 chr2: 1-5260278 0.11 Deletion Peak 7 2p21 chr2: 42587649-44009118 chr2: 43440855-43455807 chr2: 43159857-43470966 0.06 Deletion Peak 8 2q23.1 chr2: 147341956-149499455 chr2: 148437688-148750846 chr2: 148444810-148756213 0.03 Deletion Peak 9 2q37.3 chr2: 240321205-243199373 chr2: 240940975-241060875 chr2: 240589192-241997730 0.00 Deletion Peak 3p26.3 chr3: 1-8350135 chr3: 1-2251569 chr3: 1-9456413 0.03 10 Deletion Peak 3p14.2 chr3: 58946448-61555632 chr3: 59692189-61457375 chr3: 59692189-61460946 0.09 11 Deletion Peak 3p13 chr3: 70014100-71250049 chr3: 70976616-71182883 chr3: 70977475-71315576 0.11 12 Deletion Peak 3q26.31 chr3: 173995229-175766885 chr3: 174575326-175766885 chr3: 174646449-174998725 0.00 13 Deletion Peak 4p16.2 chr4: 1-9787265 chr4: 5915497-5925651 chr4: 1-11455571 0.11 14 Deletion Peak 4q22.1 chr4: 91143530-93226628 chr4: 91046982-92557520 chr4: 91103554-92561908 0.03 15 Deletion Peak 4q25 chr4: 109046573-109544048 chr4: 109451604-109544048 chr4: 109489936-109535239 0.06 16 Deletion Peak 4q31.3 chr4: 152679194-153694102 chr4: 153232273-153473069 chr4: 152233433-191154276 0.09 17 Deletion Peak 4q32.1 chr4: 156135292-162306004 chr4: 159683040-159830757 chr4: 152233433-191154276 0.06 18 Deletion Peak 4q35.1 chr4: 184432080-185262191 chr4: 184545375-185154488 chr4: 152233433-191154276 0.11 19 Deletion Peak 5p15.33 chr5: 1-2750686 chr5: 1368344-2252637 chr5: 1-3864653 0.17 20 Deletion Peak 5q12.1 chr5: 58263825-59784640 chr5: 58263825-59784640 chr5: 50968806-135478060 0.03 21 Deletion Peak 5q22.2 chr5: 111312546-112362638 chr5: 111747052-111761475 chr5: 50968806-135478060 0.06 22 Deletion Peak 6p25.3 chr6: 1613114-2256643 chr6: 1621843-2256643 chr6: 1626114-2752758 0.06 23 Deletion Peak 6p22.2 chr6: 25926929-26025173 chr6: 25932794-26025173 chr6: 25933563-26346501 0.11 24 Deletion Peak 6q21 chr6: 91006553-129206367 chr6: 111544567-112706964 chr6: 108785353-116683959 0.09 25 Deletion Peak 6q26 chr6: 161540781-163179430 chr6: 161540781-163179430 chr6: 160448048-171115067 0.14 26 Deletion Peak 7q31.1 chr7: 109590674-111367757 chr7: 110232248-111358792 chr7: 110595801-110618403 0.00 27 Deletion Peak 8p23.3 chr8: 1-1449850 chr8: 1-623109 chr8: 1-10801317 0.23 28 Deletion Peak 8p21.3 chr8: 13423967-26607015 chr8: 21547484-21647267 chr8: 11646511-25738962 0.06 29 Deletion Peak 8p12 chr8: 33445578-37452445 chr8: 34944675-36494184 chr8: 35186331-35207233 0.00 30 Deletion Peak 8q11.1 chr8: 42874387-48101823 chr8: 42931769-48061147 chr8: 42932439-48062091 0.00 31 Deletion Peak 9p21.3 chr9: 21558582-22452906 chr9: 21995318-22021004 chr9: 21711940-22331169 0.00 32 Deletion Peak 10p15.3 chr10: 1-855610 chr10: 1-418075 chr10: 1-2055670 0.06 33 Deletion Peak 10q21.1 chr10: 51561927-53481136 chr10: 51561927-54065263 chr10: 50763189-54253314 0.03 34 Deletion Peak 10q23.31 chr10: 89502327-90051809 chr10: 89574482-89607380 chr10: 83248858-135534747 0.06 35 Deletion Peak 10q25.2 chr10: 114197471-115353755 chr10: 114708532-114929210 chr10: 83248858-135534747 0.09 36 Deletion Peak 10q26.3 chr10: 133107199-135534747 chr10: 135221096-135534747 chr10: 83248858-135534747 0.23 37 Deletion Peak 11q22.3 chr11: 102958343-135006516 chr11: 108251085-108350263 chr11: 108179920-108470348 0.00 38 Deletion Peak 12p13.2 chr12: 12412186-13039757 chr12: 12525464-12721981 chr12: 11739866-13828006 0.06 39 Deletion Peak 12q21.2 chr12: 75602135-79819184 chr12: 76423769-76523220 chr12: 75648890-78593389 0.00 40 Deletion Peak 12q24.33 chr12: 125048064-133851895 chr12: 131256822-131362341 chr12: 125246979-133851895 0.14 41 Deletion Peak 14q24.1 chr14: 68280014-69351476 chr14: 68284712-68948164 chr14: 68343659-68985929 0.09 42 Deletion Peak 14q32.11 chr14: 78347564-107349540 chr14: 90999841-91286309 chr14: 90170502-92315681 0.03 43 Deletion Peak 15q11.2 chr15: 25436434-25466900 chr15: 25438412-25459423 chr15: 1-58781038 0.09 44 Deletion Peak 15q21.1 chr15: 44850582-45321541 chr15: 44851811-45052539 chr15: 1-58781038 0.06 45 Deletion Peak 15q22.33 chr15: 67053712-67697647 chr15: 67337017-67551787 chr15: 67245914-67753643 0.06 46 Deletion Peak 16p13.3 chr16: 5141600-8053542 chr16: 6056420-8053542 chr16: 5279421-7736962 0.09 47 Deletion Peak 16q23.1 chr16: 78131135-79628242 chr16: 78131135-79286336 chr16: 78424695-79295468 0.06 48 Deletion Peak 17p12 chr17: 11466949-12461211 chr17: 11872374-11906034 chr17: 10231123-12752622 0.09 49 Deletion Peak 17q24.3 chr17: 68174484-70599305 chr17: 70337175-70590424 chr17: 70549664-70552757 0.03 50 Deletion Peak 18p11.31 chr18: 3277394-4265401 chr18: 3441391-3481373 chr18: 3398771-3729936 0.00 51 Deletion Peak 18q12.2 chr18: 35136370-39061915 chr18: 36781295-37333625 chr18: 35827844-46846953 0.06 52 Deletion Peak 18q21.2 chr18: 48472034-48707815 chr18: 48547928-48660122 chr18: 47049746-78077248 0.11 53 Deletion Peak 18q21.33 chr18: 60645473-61013467 chr18: 60788090-61013467 chr18: 47049746-78077248 0.17 54 Deletion Peak 19p13.3 chr19: 1488247-1660256 chr19: 1488455-1660256 chr19: 1-5957502 0.06 55 Deletion Peak 20p12.1 chr20: 13955189-16350354 chr20: 14416445-15462745 chr20: 14096517-16064189 0.06 56 Deletion Peak 21q11.2 chr21: 15555708-16334057 chr21: 15854887-15919066 chr21: 1-31258004 0.00 57 Deletion Peak 21q21.1 chr21: 23106546-26219369 chr21: 23248652-23494410 chr21: 1-31258004 0.00 58 Deletion Peak 22q13.32 chr22: 48649199-49178363 chr22: 48906309-49158314 chr22: 47983027-51304566 0.09 59 Whole arm 10p NA NA chr10: 1-39254935 0.00 amplification 1 Whole arm 10q NA NA chr16: 1-35335801 0.00 amplification 2 Whole arm 11p NA NA chr16: 38335801-90354753 0.00 amplification 3 Whole arm 11q NA NA chr17: 1-22263006 0.00 amplification 4 Whole arm 12p NA NA chr17: 25263006-81195210 0.20 amplification 5 Whole arm 12q NA NA chr18: 1-15460898 0.17 amplification 6 Whole arm 13q NA NA chr18: 18460898-78077248 0.14 amplification 7 Whole arm 14q NA NA chr19: 1-24681782 0.03 amplification 8 Whole arm 15q NA NA chr19: 27681782-59128983 0.00 amplification 9 Whole arm 16p NA NA chr1: 1-121535434 0.09 amplification 10 Whole arm 16q NA NA chr1: 124535434-249250621 0.09 amplification 11 Whole arm 17p NA NA chr10: 42254935-135534747 0.00 amplification 12 Whole arm 17q NA NA chr20: 1-26369569 0.03 amplification 13 Whole arm 18p NA NA chr20: 29369569-63025520 0.09 amplification 14 Whole arm 18q NA NA chr21: 14288129-48129895 0.09 amplification 15 Whole arm 19p NA NA chr22: 16000000-51304566 0.17 amplification 16 Whole arm 19q NA NA chr2: 1-92326171 0.20 amplification 17 Whole arm 1p NA NA chr2: 95326171-243199373 0.00 amplification 18 Whole arm 1q NA NA chr3: 1-90504854 0.09 amplification 19 Whole arm 20p NA NA chr3: 93504854-198022430 0.00 amplification 20 Whole arm 20q NA NA chr4: 1-49660117 0.00 amplification 21 Whole arm 21q NA NA chr4: 52660117-191154276 0.00 amplification 22 Whole arm 22q NA NA chr11: 1-51644205 0.00 amplification 23 Whole arm 2p NA NA chr5: 1-46405641 0.03 amplification 24 Whole arm 2q NA NA chr5: 49405641-180915260 0.03 amplification 25 Whole arm 3p NA NA chr6: 1-58830166 0.06 amplification 26 Whole arm 3q NA NA chr6: 61830166-171115067 0.06 amplification 27 Whole arm 4p NA NA chr7: 1-58054331 0.00 amplification 28 Whole arm 4q NA NA chr7: 61054331-159138663 0.00 amplification 29 Whole arm 5p NA NA chr8: 1-43838887 0.00 amplification 30 Whole arm 5q NA NA chr8: 46838887-146364022 0.00 amplification 31 Whole arm 6p NA NA chr9: 1-47367679 0.06 amplification 32 Whole arm 6q NA NA chr9: 50367679-141213431 0.06 amplification 33 Whole arm 7p NA NA chr11: 54644205-135006516 0.34 amplification 34 Whole arm 7q NA NA chr12: 1-34856694 0.34 amplification 35 Whole arm 8p NA NA chr12: 37856694-133851895 0.14 amplification 36 Whole arm 8q NA NA chr13: 19000000-115169878 0.23 amplification 37 Whole arm 9p NA NA chr14: 19000000-107349540 0.06 amplification 38 Whole arm 9q NA NA chr15: 20000000-102531392 0.06 amplification 39 Whole arm 10p NA NA chr10: 1-39254935 0.03 deletion 1 Whole arm 10q NA NA chr16: 1-35335801 0.00 deletion 2 Whole arm 11p NA NA chr16: 38335801-90354753 0.00 deletion 3 Whole arm 11q NA NA chr17: 1-22263006 0.00 deletion 4 Whole arm 12p NA NA chr17: 25263006-81195210 0.00 deletion 5 Whole arm 12q NA NA chr18: 1-15460898 0.00 deletion 6 Whole arm 13q NA NA chr18: 18460898-78077248 0.00 deletion 7 Whole arm 14q NA NA chr19: 1-24681782 0.00 deletion 8 Whole arm 15q NA NA chr19: 27681782-59128983 0.03 deletion 9 Whole arm 16p NA NA chr1: 1-121535434 0.06 deletion 10 Whole arm 16q NA NA chr1: 124535434-249250621 0.03 deletion 11 Whole arm 17p NA NA chr10: 42254935-135534747 0.09 deletion 12 Whole arm 17q NA NA chr20: 1-26369569 0.03 deletion 13 Whole arm 18p NA NA chr20: 29369569-63025520 0.03 deletion 14 Whole arm 18q NA NA chr21: 14288129-48129895 0.06 deletion 15 Whole arm 19p NA NA chr22: 16000000-51304566 0.06 deletion 16 Whole arm 19q NA NA chr2: 1-92326171 0.06 deletion 17 Whole arm 1p NA NA chr2: 95326171-243199373 0.03 deletion 18 Whole arm 1q NA NA chr3: 1-90504854 0.00 deletion 19 Whole arm 20p NA NA chr3: 93504854-198022430 0.03 deletion 20 Whole arm 20q NA NA chr4: 1-49660117 0.00 deletion 21 Whole arm 21q NA NA chr4: 52660117-191154276 0.00 deletion 22 Whole arm 22q NA NA chr11: 1-51644205 0.09 deletion 23 Whole arm 2p NA NA chr5: 1-46405641 0.00 deletion 24 Whole arm 2q NA NA chr5: 49405641-180915260 0.00 deletion 25 Whole arm 3p NA NA chr6: 1-58830166 0.00 deletion 26 Whole arm 3q NA NA chr6: 61830166-171115067 0.00 deletion 27 Whole arm 4p NA NA chr7: 1-58054331 0.00 deletion 28 Whole arm 4q NA NA chr7: 61054331-159138663 0.03 deletion 29 Whole arm 5p NA NA chr8: 1-43838887 0.03 deletion 30 Whole arm 5q NA NA chr8: 46838887-146364022 0.03 deletion 31 Whole arm 6p NA NA chr9: 1-47367679 0.03 deletion 32 Whole arm 6q NA NA chr9: 50367679-141213431 0.03 deletion 33 Whole arm 7p NA NA chr11: 54644205-135006516 0.00 deletion 34 Whole arm 7q NA NA chr12: 1-34856694 0.00 deletion 35 Whole arm 8p NA NA chr12: 37856694-133851895 0.03 deletion 36 Whole arm 8q NA NA chr13: 19000000-115169878 0.00 deletion 37 Whole arm 9p NA NA chr14: 19000000-107349540 0.00 deletion 38 Whole arm 9q NA NA chr15: 20000000-102531392 0.00 deletion 39

TABLE 3 The copy number alteration specifications of cluster 2 (genetic subtype 2). All genomic regions of the biomarker panel of Table 1 are listed together with the frequency that these regions are affected in cluster 2. Frequency of region being affected in Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits cluster 2 Amplification 1p34.2 chr1: 39144054-44367347 chr1: 42834925-43114106 chr1: 42692914-43456374 0.04 Peak 1 Amplification 1q22 chr1: 120494739-199253746 chr1: 155143717-155177826 chr1: 120497533-175439985 0.29 Peak 2 Amplification 1q43 chr1: 201615295-249250621 chr1: 242413158-242638099 chr1: 242270003-249250621 0.30 Peak 3 Amplification 2q33.1 chr2: 181446594-243199373 chr2: 199603526-199649638 chr2: 199525178-199824262 0.23 Peak 4 Amplification 3q29 chr3: 174745992-198022430 chr3: 195922177-195991311 chr3: 174746836-198022430 0.19 Peak 5 Amplification 5p15.33 chr5: 1-6418038 chr5: 1-949725 chr5: 1-2807521 0.20 Peak 6 Amplification 5p12 chr5: 33430780-50470114 chr5: 43822799-43929095 chr5: 37334807-44266311 0.18 Peak 7 Amplification 6p21.1 chr6: 43545080-44164949 chr6: 43765716-44163738 chr6: 36748055-52028937 0.23 Peak 8 Amplification 6q23.3 chr6: 135342981-135632150 chr6: 135513416-135593890 chr6: 133418393-138096856 0.18 Peak 9 Amplification 7p11.2 chr7: 54949302-55950640 chr7: 55248172-55271747 chr7: 54949902-55955413 0.63 Peak 10 Amplification 8p11.23 chr8: 38162916-38237532 chr8: 38165117-38236937 chr8: 34342520-48854434 0.42 Peak 11 Amplification 8p11.21 chr8: 41760295-42054539 chr8: 41767516-41796226 chr8: 34342520-48854434 0.55 Peak 12 Amplification 8q12.2 chr8: 60847395-62906825 chr8: 61658252-61874896 chr8: 54646329-146364022 0.68 Peak 13 Amplification 8q21.13 chr8: 80636493-82552412 chr8: 81853752-81935079 chr8: 54646329-146364022 0.74 Peak 14 Amplification 8q22.3 chr8: 101853171-101878037 chr8: 101853464-101876083 chr8: 54646329-146364022 0.76 Peak 15 Amplification 8q24.21 chr8: 128574277-128592142 chr8: 128574768-128591041 chr8: 54646329-146364022 0.77 Peak 16 Amplification 10q22.3 chr10: 79956009-83248579 chr10: 80445049-80732930 chr10: 77952482-83583616 0.04 Peak 17 Amplification 11p15.5 chr11: 2091739-2302637 chr11: 2095340-2301396 chr11: 2095340-2305324 0.10 Peak 18 Amplification 11q13.3 chr11: 68746750-69827851 chr11: 69311828-69824706 chr11: 68748468-70760456 0.09 Peak 19 Amplification 12p13.32 chr12: 3941807-4552801 chr12: 4257035-4414967 chr12: 1-8970181 0.31 Peak 20 Amplification 12p11.22 chr12: 24880798-28477058 chr12: 27800441-27813180 chr12: 25955987-28156868 0.31 Peak 21 Amplification 13q12.2 chr13: 28164386-28564331 chr13: 28174614-28222659 chr13: 1-115169878 0.82 Peak 22 Amplification 13q22.1 chr13: 73775176-74007122 chr13: 73906681-74004816 chr13: 1-115169878 0.79 Peak 23 Amplification 13q34 chr13: 110097815-111753132 chr13: 110614601-110852082 chr13: 1-115169878 0.78 Peak 24 Amplification 15q26.1 chr15: 84648780-102531392 chr15: 90811423-90958538 chr15: 90086447-91895585 0.06 Peak 25 Amplification 16p11.2 chr16: 30548665-30684980 chr16: 30549334-30682578 chr16: 28556705-46663588 0.36 Peak 26 Amplification 16q12.1 chr16: 52243935-52652774 chr16: 52383686-52652198 chr16: 51078632-53117566 0.29 Peak 27 Amplification 17q11.2 chr17: 27339261-27528113 chr17: 27339592-27419750 chr17: 20042949-40168023 0.24 Peak 28 Amplification 17q12 chr17: 37747533-38052599 chr17: 37950674-38031986 chr17: 20042949-40168023 0.22 Peak 29 Amplification 17q23.2 chr17: 58400463-58674819 chr17: 58400997-58532661 chr17: 57045336-62714320 0.21 Peak 30 Amplification 17q24.2 chr17: 65638523-65873408 chr17: 65649475-65769071 chr17: 63042470-68655121 0.21 Peak 31 Amplification 17q25.3 chr17: 77601682-77857881 chr17: 77766436-77856811 chr17: 75845339-81195210 0.22 Peak 32 Amplification 18q11.2 chr18: 19517253-20155059 chr18: 19525020-20154578 chr18: 19243919-21268418 0.06 Peak 33 Amplification 18q21.1 chr18: 46041609-46930382 chr18: 46474762-46604295 chr18: 46043163-46624631 0.04 Peak 34 Amplification 19q13.11 chr19: 32439834-33021877 chr19: 32966965-32988344 chr19: 19939350-41312227 0.19 Peak 35 Amplification 19q13.2 chr19: 39844313-40357920 chr19: 39848086-40009185 chr19: 19939350-41312227 0.18 Peak 36 Amplification 20p12.3 chr20: 5376354-5742957 chr20: 5379141-5737687 chr20: 5156552-5961498 0.42 Peak 37 Amplification 20p12.1 chr20: 16140291-16967195 chr20: 16488303-16962609 chr20: 16146669-16970141 0.46 Peak 38 Amplification 20p11.22 chr20: 22058560-22353663 chr20: 22063756-22350551 chr20: 20938975-24286806 0.55 Peak 39 Amplification 20q11.21 chr20: 29981165-30284236 chr20: 30158807-30231055 chr20: 24375411-63025520 0.94 Peak 40 Amplification 20q13.12 chr20: 42534268-43281676 chr20: 42537604-42773258 chr20: 24375411-63025520 0.93 Peak 41 Amplification 20q13.2 chr20: 52240629-52852159 chr20: 52246659-52447690 chr20: 24375411-63025520 0.95 Peak 42 Amplification 20q13.32 chr20: 56110288-57258354 chr20: 57000076-57085518 chr20: 24375411-63025520 0.95 Peak 43 Deletion Peak 1 1p36.31 chr1: 4843384-6053964 chr1: 5646446-6050774 chr1: 1-37080378 0.40 Deletion Peak 2 1p36.11 chr1: 26898389-27219375 chr1: 27139248-27185402 chr1: 1-37080378 0.42 Deletion Peak 3 1p33 chr1: 49187432-50544677 chr1: 48847112-50490440 chr1: 49196205-51396500 0.19 Deletion Peak 4 1p31.1 chr1: 68959091-82269682 chr1: 79308665-79566142 chr1: 54944113-149961894 0.21 Deletion Peak 5 1p21.1 chr1: 102460262-107618224 chr1: 104041213-104355050 chr1: 54944113-149961894 0.22 Deletion Peak 6 2p25.3 chr2: 1-4752017 chr2: 1-488785 chr2: 1-5260278 0.13 Deletion Peak 7 2p21 chr2: 42587649-44009118 chr2: 43440855-43455807 chr2: 43159857-43470966 0.01 Deletion Peak 8 2q23.1 chr2: 147341956-149499455 chr2: 148437688-148750846 chr2: 148444810-148756213 0.04 Deletion Peak 9 2q37.3 chr2: 240321205-243199373 chr2: 240940975-241060875 chr2: 240589192-241997730 0.05 Deletion Peak 3p26.3 chr3: 1-8350135 chr3: 1-2251569 chr3: 1-9456413 0.18 10 Deletion Peak 3p14.2 chr3: 58946448-61555632 chr3: 59692189-61457375 chr3: 59692189-61460946 0.15 11 Deletion Peak 3p13 chr3: 70014100-71250049 chr3: 70976616-71182883 chr3: 70977475-71315576 0.15 12 Deletion Peak 3q26.31 chr3: 173995229-175766885 chr3: 174575326-175766885 chr3: 174646449-174998725 0.02 13 Deletion Peak 4p16.2 chr4: 1-9787265 chr4: 5915497-5925651 chr4: 1-11455571 0.24 14 Deletion Peak 4q22.1 chr4: 91143530-93226628 chr4: 91046982-92557520 chr4: 91103554-92561908 0.10 15 Deletion Peak 4q25 chr4: 109046573-109544048 chr4: 109451604-109544048 chr4: 109489936-109535239 0.08 16 Deletion Peak 4q31.3 chr4: 152679194-153694102 chr4: 153232273-153473069 chr4: 152233433-191154276 0.06 17 Deletion Peak 4q32.1 chr4: 156135292-162306004 chr4: 159683040-159830757 chr4: 152233433-191154276 0.09 18 Deletion Peak 4q35.1 chr4: 184432080-185262191 chr4: 184545375-185154488 chr4: 152233433-191154276 0.13 19 Deletion Peak 5p15.33 chr5: 1-2750686 chr5: 1368344-2252637 chr5: 1-3864653 0.20 20 Deletion Peak 5q12.1 chr5: 58263825-59784640 chr5: 58263825-59784640 chr5: 50968806-135478060 0.12 21 Deletion Peak 5q22.2 chr5: 111312546-112362638 chr5: 111747052-111761475 chr5: 50968806-135478060 0.21 22 Deletion Peak 6p25.3 chr6: 1613114-2256643 chr6: 1621843-2256643 chr6: 1626114-2752758 0.06 23 Deletion Peak 6p22.2 chr6: 25926929-26025173 chr6: 25932794-26025173 chr6: 25933563-26346501 0.06 24 Deletion Peak 6q21 chr6: 91006553-129206367 chr6: 111544567-112706964 chr6: 108785353-116683959 0.12 25 Deletion Peak 6q26 chr6: 161540781-163179430 chr6: 161540781-163179430 chr6: 160448048-171115067 0.17 26 Deletion Peak 7q31.1 chr7: 109590674-111367757 chr7: 110232248-111358792 chr7: 110595801-110618403 0.02 27 Deletion Peak 8p23.3 chr8: 1-1449850 chr8: 1-623109 chr8: 1-10801317 0.59 28 Deletion Peak 8p21.3 chr8: 13423967-26607015 chr8: 21547484-21647267 chr8: 11646511-25738962 0.58 29 Deletion Peak 8p12 chr8: 33445578-37452445 chr8: 34944675-36494184 chr8: 35186331-35207233 0.46 30 Deletion Peak 8q11.1 chr8: 42874387-48101823 chr8: 42931769-48061147 chr8: 42932439-48062091 0.03 31 Deletion Peak 9p21.3 chr9: 21558582-22452906 chr9: 21995318-22021004 chr9: 21711940-22331169 0.09 32 Deletion Peak 10p15.3 chr10: 1-855610 chr10: 1-418075 chr10: 1-2055670 0.09 33 Deletion Peak 10q21.1 chr10: 51561927-53481136 chr10: 51561927-54065263 chr10: 50763189-54253314 0.07 34 Deletion Peak 10q23.31 chr10: 89502327-90051809 chr10: 89574482-89607380 chr10: 83248858-135534747 0.14 35 Deletion Peak 10q25.2 chr10: 114197471-115353755 chr10: 114708532-114929210 chr10: 83248858-135534747 0.09 36 Deletion Peak 10q26.3 chr10: 133107199-135534747 chr10: 135221096-135534747 chr10: 83248858-135534747 0.20 37 Deletion Peak 11q22.3 chr11: 102958343-135006516 chr11: 108251085-108350263 chr11: 108179920-108470348 0.08 38 Deletion Peak 12p13.2 chr12: 12412186-13039757 chr12: 12525464-12721981 chr12: 11739866-13828006 0.10 39 Deletion Peak 12q21.2 chr12: 75602135-79819184 chr12: 76423769-76523220 chr12: 75648890-78593389 0.02 40 Deletion Peak 12q24.33 chr12: 125048064-133851895 chr12: 131256822-131362341 chr12: 125246979-133851895 0.15 41 Deletion Peak 14q24.1 chr14: 68280014-69351476 chr14: 68284712-68948164 chr14: 68343659-68985929 0.24 42 Deletion Peak 14q32.11 chr14: 78347564-107349540 chr14: 90999841-91286309 chr14: 90170502-92315681 0.22 43 Deletion Peak 15q11.2 chr15: 25436434-25466900 chr15: 25438412-25459423 chr15: 1-58781038 0.30 44 Deletion Peak 15q21.1 chr15: 44850582-45321541 chr15: 44851811-45052539 chr15: 1-58781038 0.26 45 Deletion Peak 15q22.33 chr15: 67053712-67697647 chr15: 67337017-67551787 chr15: 67245914-67753643 0.21 46 Deletion Peak 16p13.3 chr16: 5141600-8053542 chr16: 6056420-8053542 chr16: 5279421-7736962 0.08 47 Deletion Peak 16q23.1 chr16: 78131135-79628242 chr16: 78131135-79286336 chr16: 78424695-79295468 0.05 48 Deletion Peak 17p12 chr17: 11466949-12461211 chr17: 11872374-11906034 chr17: 10231123-12752622 0.63 49 Deletion Peak 17q24.3 chr17: 68174484-70599305 chr17: 70337175-70590424 chr17: 70549664-70552757 0.13 50 Deletion Peak 18p11.31 chr18: 3277394-4265401 chr18: 3441391-3481373 chr18: 3398771-3729936 0.59 51 Deletion Peak 18q12.2 chr18: 35136370-39061915 chr18: 36781295-37333625 chr18: 35827844-46846953 0.81 52 Deletion Peak 18q21.2 chr18: 48472034-48707815 chr18: 48547928-48660122 chr18: 47049746-78077248 0.83 53 Deletion Peak 18q21.33 chr18: 60645473-61013467 chr18: 60788090-61013467 chr18: 47049746-78077248 0.82 54 Deletion Peak 19p13.3 chr19: 1488247-1660256 chr19: 1488455-1660256 chr19: 1-5957502 0.05 55 Deletion Peak 20p12.1 chr20: 13955189-16350354 chr20: 14416445-15462745 chr20: 14096517-16064189 0.33 56 Deletion Peak 21q11.2 chr21: 15555708-16334057 chr21: 15854887-15919066 chr21: 1-31258004 0.12 57 Deletion Peak 21q21.1 chr21: 23106546-26219369 chr21: 23248652-23494410 chr21: 1-31258004 0.14 58 Deletion Peak 22q13.32 chr22: 48649199-49178363 chr22: 48906309-49158314 chr22: 47983027-51304566 0.31 59 Whole arm 10p NA NA chr10: 1-39254935 0.14 amplification 1 Whole arm 10q NA NA chr16: 1-35335801 0.04 amplification 2 Whole arm 11p NA NA chr16: 38335801-90354753 0.06 amplification 3 Whole arm 11q NA NA chr17: 1-22263006 0.07 amplification 4 Whole arm 12p NA NA chr17: 25263006-81195210 0.29 amplification 5 Whole arm 12q NA NA chr18: 1-15460898 0.20 amplification 6 Whole arm 13q NA NA chr18: 18460898-78077248 0.78 amplification 7 Whole arm 14q NA NA chr19: 1-24681782 0.06 amplification 8 Whole arm 15q NA NA chr19: 27681782-59128983 0.03 amplification 9 Whole arm 16p NA NA chr1: 1-121535434 0.29 amplification 10 Whole arm 16q NA NA chr1: 124535434-249250621 0.28 amplification 11 Whole arm 17p NA NA chr10: 42254935-135534747 0.02 amplification 12 Whole arm 17q NA NA chr20: 1-26369569 0.13 amplification 13 Whole arm 18p NA NA chr20: 29369569-63025520 0.05 amplification 14 Whole arm 18q NA NA chr21: 14288129-48129895 0.01 amplification 15 Whole arm 19p NA NA chr22: 16000000-51304566 0.15 amplification 16 Whole arm 19q NA NA chr2: 1-92326171 0.18 amplification 17 Whole arm 1p NA NA chr2: 95326171-243199373 0.01 amplification 18 Whole arm 1q NA NA chr3: 1-90504854 0.23 amplification 19 Whole arm 20p NA NA chr3: 93504854-198022430 0.50 amplification 20 Whole arm 20q NA NA chr4: 1-49660117 0.90 amplification 21 Whole arm 21q NA NA chr4: 52660117-191154276 0.06 amplification 22 Whole arm 22q NA NA chr11: 1-51644205 0.01 amplification 23 Whole arm 2p NA NA chr5: 1-46405641 0.18 amplification 24 Whole arm 2q NA NA chr5: 49405641-180915260 0.19 amplification 25 Whole arm 3p NA NA chr6: 1-58830166 0.05 amplification 26 Whole arm 3q NA NA chr6: 61830166-171115067 0.14 amplification 27 Whole arm 4p NA NA chr7: 1-58054331 0.03 amplification 28 Whole arm 4q NA NA chr7: 61054331-159138663 0.02 amplification 29 Whole arm 5p NA NA chr8: 1-43838887 0.17 amplification 30 Whole arm 5q NA NA chr8: 46838887-146364022 0.11 amplification 31 Whole arm 6p NA NA chr9: 1-47367679 0.16 amplification 32 Whole arm 6q NA NA chr9: 50367679-141213431 0.15 amplification 33 Whole arm 7p NA NA chr11: 54644205-135006516 0.63 amplification 34 Whole arm 7q NA NA chr12: 1-34856694 0.54 amplification 35 Whole arm 8p NA NA chr12: 37856694-133851895 0.20 amplification 36 Whole arm 8q NA NA chr13: 19000000-115169878 0.69 amplification 37 Whole arm 9p NA NA chr14: 19000000-107349540 0.16 amplification 38 Whole arm 9q NA NA chr15: 20000000-102531392 0.17 amplification 39 Whole arm 10p NA NA chr10: 1-39254935 0.04 deletion 1 Whole arm 10q NA NA chr16: 1-35335801 0.07 deletion 2 Whole arm 11p NA NA chr16: 38335801-90354753 0.01 deletion 3 Whole arm 11q NA NA chr17: 1-22263006 0.04 deletion 4 Whole arm 12p NA NA chr17: 25263006-81195210 0.04 deletion 5 Whole arm 12q NA NA chr18: 1-15460898 0.01 deletion 6 Whole arm 13q NA NA chr18: 18460898-78077248 0.02 deletion 7 Whole arm 14q NA NA chr19: 1-24681782 0.21 deletion 8 Whole arm 15q NA NA chr19: 27681782-59128983 0.21 deletion 9 Whole arm 16p NA NA chr1: 1-121535434 0.03 deletion 10 Whole arm 16q NA NA chr1: 124535434-249250621 0.02 deletion 11 Whole arm 17p NA NA chr10: 42254935-135534747 0.57 deletion 12 Whole arm 17q NA NA chr20: 1-26369569 0.05 deletion 13 Whole arm 18p NA NA chr20: 29369569-63025520 0.62 deletion 14 Whole arm 18q NA NA chr21: 14288129-48129895 0.79 deletion 15 Whole arm 19p NA NA chr22: 16000000-51304566 0.02 deletion 16 Whole arm 19q NA NA chr2: 1-92326171 0.01 deletion 17 Whole arm 1p NA NA chr2: 95326171-243199373 0.17 deletion 18 Whole arm 1q NA NA chr3: 1-90504854 0.01 deletion 19 Whole arm 20p NA NA chr3: 93504854-198022430 0.19 deletion 20 Whole arm 20q NA NA chr4: 1-49660117 0.00 deletion 21 Whole arm 21q NA NA chr4: 52660117-191154276 0.10 deletion 22 Whole arm 22q NA NA chr11: 1-51644205 0.21 deletion 23 Whole arm 2p NA NA chr5: 1-46405641 0.01 deletion 24 Whole arm 2q NA NA chr5: 49405641-180915260 0.01 deletion 25 Whole arm 3p NA NA chr6: 1-58830166 0.10 deletion 26 Whole arm 3q NA NA chr6: 61830166-171115067 0.02 deletion 27 Whole arm 4p NA NA chr7: 1-58054331 0.12 deletion 28 Whole arm 4q NA NA chr7: 61054331-159138663 0.05 deletion 29 Whole arm 5p NA NA chr8: 1-43838887 0.03 deletion 30 Whole arm 5q NA NA chr8: 46838887-146364022 0.06 deletion 31 Whole arm 6p NA NA chr9: 1-47367679 0.02 deletion 32 Whole arm 6q NA NA chr9: 50367679-141213431 0.06 deletion 33 Whole arm 7p NA NA chr11: 54644205-135006516 0.00 deletion 34 Whole arm 7q NA NA chr12: 1-34856694 0.00 deletion 35 Whole arm 8p NA NA chr12: 37856694-133851895 0.39 deletion 36 Whole arm 8q NA NA chr13: 19000000-115169878 0.02 deletion 37 Whole arm 9p NA NA chr14: 19000000-107349540 0.03 deletion 38 Whole arm 9q NA NA chr15: 20000000-102531392 0.03 deletion 39

TABLE 4 The copy number alteration specifications of cluster 3 (genetic subtype 3). All genomic regions of the biomarker panel of Table 1 are listed together with the frequency that these regions are affected in cluster 3. Frequency of region being affected in Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits cluster 3 Amplification 1p34.2 chr1: 39144054-44367347 chr1: 42834925-43114106 chr1: 42692914-43456374 0.06 Peak 1 Amplification 1q22 chr1: 120494739-199253746 chr1: 155143717-155177826 chr1: 120497533-175439985 0.42 Peak 2 Amplification 1q43 chr1: 201615295-249250621 chr1: 242413158-242638099 chr1: 242270003-249250621 0.39 Peak 3 Amplification 2q33.1 chr2: 181446594-243199373 chr2: 199603526-199649638 chr2: 199525178-199824262 0.29 Peak 4 Amplification 3q29 chr3: 174745992-198022430 chr3: 195922177-195991311 chr3: 174746836-198022430 0.31 Peak 5 Amplification 5p15.33 chr5: 1-6418038 chr5: 1-949725 chr5: 1-2807521 0.33 Peak 6 Amplification 5p12 chr5: 33430780-50470114 chr5: 43822799-43929095 chr5: 37334807-44266311 0.35 Peak 7 Amplification 6p21.1 chr6: 43545080-44164949 chr6: 43765716-44163738 chr6: 36748055-52028937 0.45 Peak 8 Amplification 6q23.3 chr6: 135342981-135632150 chr6: 135513416-135593890 chr6: 133418393-138096856 0.31 Peak 9 Amplification 7p11.2 chr7: 54949302-55950640 chr7: 55248172-55271747 chr7: 54949902-55955413 0.77 Peak 10 Amplification 8p11.23 chr8: 38162916-38237532 chr8: 38165117-38236937 chr8: 34342520-48854434 0.29 Peak 11 Amplification 8p11.21 chr8: 41760295-42054539 chr8: 41767516-41796226 chr8: 34342520-48854434 0.43 Peak 12 Amplification 8q12.2 chr8: 60847395-62906825 chr8: 61658252-61874896 chr8: 54646329-146364022 0.54 Peak 13 Amplification 8q21.13 chr8: 80636493-82552412 chr8: 81853752-81935079 chr8: 54646329-146364022 0.56 Peak 14 Amplification 8q22.3 chr8: 101853171-101878037 chr8: 101853464-101876083 chr8: 54646329-146364022 0.59 Peak 15 Amplification 8q24.21 chr8: 128574277-128592142 chr8: 128574768-128591041 chr8: 54646329-146364022 0.63 Peak 16 Amplification 10q22.3 chr10: 79956009-83248579 chr10: 80445049-80732930 chr10: 77952482-83583616 0.07 Peak 17 Amplification 11p15.5 chr11: 2091739-2302637 chr11: 2095340-2301396 chr11: 2095340-2305324 0.30 Peak 18 Amplification 11q13.3 chr11: 68746750-69827851 chr11: 69311828-69824706 chr11: 68748468-70760456 0.19 Peak 19 Amplification 12p13.32 chr12: 3941807-4552801 chr12: 4257035-4414967 chr12: 1-8970181 0.31 Peak 20 Amplification 12p11.22 chr12: 24880798-28477058 chr12: 27800441-27813180 chr12: 25955987-28156868 0.27 Peak 21 Amplification 13q12.2 chr13: 28164386-28564331 chr13: 28174614-28222659 chr13: 1-115169878 0.85 Peak 22 Amplification 13q22.1 chr13: 73775176-74007122 chr13: 73906681-74004816 chr13: 1-115169878 0.84 Peak 23 Amplification 13q34 chr13: 110097815-111753132 chr13: 110614601-110852082 chr13: 1-115169878 0.81 Peak 24 Amplification 15q26.1 chr15: 84648780-102531392 chr15: 90811423-90958538 chr15: 90086447-91895585 0.11 Peak 25 Amplification 16p11.2 chr16: 30548665-30684980 chr16: 30549334-30682578 chr16: 28556705-46663588 0.57 Peak 26 Amplification 16q12.1 chr16: 52243935-52652774 chr16: 52383686-52652198 chr16: 51078632-53117566 0.48 Peak 27 Amplification 17q11.2 chr17: 27339261-27528113 chr17: 27339592-27419750 chr17: 20042949-40168023 0.30 Peak 28 Amplification 17q12 chr17: 37747533-38052599 chr17: 37950674-38031986 chr17: 20042949-40168023 0.30 Peak 29 Amplification 17q23.2 chr17: 58400463-58674819 chr17: 58400997-58532661 chr17: 57045336-62714320 0.28 Peak 30 Amplification 17q24.2 chr17: 65638523-65873408 chr17: 65649475-65769071 chr17: 63042470-68655121 0.29 Peak 31 Amplification 17q25.3 chr17: 77601682-77857881 chr17: 77766436-77856811 chr17: 75845339-81195210 0.29 Peak 32 Amplification 18q11.2 chr18: 19517253-20155059 chr18: 19525020-20154578 chr18: 19243919-21268418 0.07 Peak 33 Amplification 18q21.1 chr18: 46041609-46930382 chr18: 46474762-46604295 chr18: 46043163-46624631 0.04 Peak 34 Amplification 19q13.11 chr19: 32439834-33021877 chr19: 32966965-32988344 chr19: 19939350-41312227 0.35 Peak 35 Amplification 19q13.2 chr19: 39844313-40357920 chr19: 39848086-40009185 chr19: 19939350-41312227 0.34 Peak 36 Amplification 20p12.3 chr20: 5376354-5742957 chr20: 5379141-5737687 chr20: 5156552-5961498 0.59 Peak 37 Amplification 20p12.1 chr20: 16140291-16967195 chr20: 16488303-16962609 chr20: 16146669-16970141 0.65 Peak 38 Amplification 20p11.22 chr20: 22058560-22353663 chr20: 22063756-22350551 chr20: 20938975-24286806 0.71 Peak 39 Amplification 20q11.21 chr20: 29981165-30284236 chr20: 30158807-30231055 chr20: 24375411-63025520 0.95 Peak 40 Amplification 20q13.12 chr20: 42534268-43281676 chr20: 42537604-42773258 chr20: 24375411-63025520 0.94 Peak 41 Amplification 20q13.2 chr20: 52240629-52852159 chr20: 52246659-52447690 chr20: 24375411-63025520 0.95 Peak 42 Amplification 20q13.32 chr20: 56110288-57258354 chr20: 57000076-57085518 chr20: 24375411-63025520 0.95 Peak 43 Deletion Peak 1 1p36.31 chr1: 4843384-6053964 chr1: 5646446-6050774 chr1: 1-37080378 0.62 Deletion Peak 2 1p36.11 chr1: 26898389-27219375 chr1: 27139248-27185402 chr1: 1-37080378 0.68 Deletion Peak 3 1p33 chr1: 49187432-50544677 chr1: 48847112-50490440 chr1: 49196205-51396500 0.59 Deletion Peak 4 1p31.1 chr1: 68959091-82269682 chr1: 79308665-79566142 chr1: 54944113-149961894 0.63 Deletion Peak 5 1p21.1 chr1: 102460262-107618224 chr1: 104041213-104355050 chr1: 54944113-149961894 0.66 Deletion Peak 6 2p25.3 chr2: 1-4752017 chr2: 1-488785 chr2: 1-5260278 0.22 Deletion Peak 7 2p21 chr2: 42587649-44009118 chr2: 43440855-43455807 chr2: 43159857-43470966 0.09 Deletion Peak 8 2q23.1 chr2: 147341956-149499455 chr2: 148437688-148750846 chr2: 148444810-148756213 0.08 Deletion Peak 9 2q37.3 chr2: 240321205-243199373 chr2: 240940975-241060875 chr2: 240589192-241997730 0.11 Deletion Peak 3p26.3 chr3: 1-8350135 chr3: 1-2251569 chr3: 1-9456413 0.33 10 Deletion Peak 3p14.2 chr3: 58946448-61555632 chr3: 59692189-61457375 chr3: 59692189-61460946 0.28 11 Deletion Peak 3p13 chr3: 70014100-71250049 chr3: 70976616-71182883 chr3: 70977475-71315576 0.32 12 Deletion Peak 3q26.31 chr3: 173995229-175766885 chr3: 174575326-175766885 chr3: 174646449-174998725 0.10 13 Deletion Peak 4p16.2 chr4: 1-9787265 chr4: 5915497-5925651 chr4: 1-11455571 0.72 14 Deletion Peak 4q22.1 chr4: 91143530-93226628 chr4: 91046982-92557520 chr4: 91103554-92561908 0.74 15 Deletion Peak 4q25 chr4: 109046573-109544048 chr4: 109451604-109544048 chr4: 109489936-109535239 0.74 16 Deletion Peak 4q31.3 chr4: 152679194-153694102 chr4: 153232273-153473069 chr4: 152233433-191154276 0.74 17 Deletion Peak 4q32.1 chr4: 156135292-162306004 chr4: 159683040-159830757 chr4: 152233433-191154276 0.76 18 Deletion Peak 4q35.1 chr4: 184432080-185262191 chr4: 184545375-185154488 chr4: 152233433-191154276 0.78 19 Deletion Peak 5p15.33 chr5: 1-2750686 chr5: 1368344-2252637 chr5: 1-3864653 0.29 20 Deletion Peak 5q12.1 chr5: 58263825-59784640 chr5: 58263825-59784640 chr5: 50968806-135478060 0.45 21 Deletion Peak 5q22.2 chr5: 111312546-112362638 chr5: 111747052-111761475 chr5: 50968806-135478060 0.50 22 Deletion Peak 6p25.3 chr6: 1613114-2256643 chr6: 1621843-2256643 chr6: 1626114-2752758 0.18 23 Deletion Peak 6p22.2 chr6: 25926929-26025173 chr6: 25932794-26025173 chr6: 25933563-26346501 0.18 24 Deletion Peak 6q21 chr6: 91006553-129206367 chr6: 111544567-112706964 chr6: 108785353-116683959 0.25 25 Deletion Peak 6q26 chr6: 161540781-163179430 chr6: 161540781-163179430 chr6: 160448048-171115067 0.31 26 Deletion Peak 7q31.1 chr7: 109590674-111367757 chr7: 110232248-111358792 chr7: 110595801-110618403 0.05 27 Deletion Peak 8p23.3 chr8: 1-1449850 chr8: 1-623109 chr8: 1-10801317 0.79 28 Deletion Peak 8p21.3 chr8: 13423967-26607015 chr8: 21547484-21647267 chr8: 11646511-25738962 0.76 29 Deletion Peak 8p12 chr8: 33445578-37452445 chr8: 34944675-36494184 chr8: 35186331-35207233 0.57 30 Deletion Peak 8q11.1 chr8: 42874387-48101823 chr8: 42931769-48061147 chr8: 42932439-48062091 0.13 31 Deletion Peak 9p21.3 chr9: 21558582-22452906 chr9: 21995318-22021004 chr9: 21711940-22331169 0.20 32 Deletion Peak 10p15.3 chr10: 1-855610 chr10: 1-418075 chr10: 1-2055670 0.32 33 Deletion Peak 10q21.1 chr10: 51561927-53481136 chr10: 51561927-54065263 chr10: 50763189-54253314 0.47 34 Deletion Peak 10q23.31 chr10: 89502327-90051809 chr10: 89574482-89607380 chr10: 83248858-135534747 0.53 35 Deletion Peak 10q25.2 chr10: 114197471-115353755 chr10: 114708532-114929210 chr10: 83248858-135534747 0.49 36 Deletion Peak 10q26.3 chr10: 133107199-135534747 chr10: 135221096-135534747 chr10: 83248858-135534747 0.56 37 Deletion Peak 11q22.3 chr11: 102958343-135006516 chr11: 108251085-108350263 chr11: 108179920-108470348 0.37 38 Deletion Peak 12p13.2 chr12: 12412186-13039757 chr12: 12525464-12721981 chr12: 11739866-13828006 0.22 39 Deletion Peak 12q21.2 chr12: 75602135-79819184 chr12: 76423769-76523220 chr12: 75648890-78593389 0.25 40 Deletion Peak 12q24.33 chr12: 125048064-133851895 chr12: 131256822-131362341 chr12: 125246979-133851895 0.33 41 Deletion Peak 14q24.1 chr14: 68280014-69351476 chr14: 68284712-68948164 chr14: 68343659-68985929 0.58 42 Deletion Peak 14q32.11 chr14: 78347564-107349540 chr14: 90999841-91286309 chr14: 90170502-92315681 0.55 43 Deletion Peak 15q11.2 chr15: 25436434-25466900 chr15: 25438412-25459423 chr15: 1-58781038 0.70 44 Deletion Peak 15q21.1 chr15: 44850582-45321541 chr15: 44851811-45052539 chr15: 1-58781038 0.66 45 Deletion Peak 15q22.33 chr15: 67053712-67697647 chr15: 67337017-67551787 chr15: 67245914-67753643 0.67 46 Deletion Peak 16p13.3 chr16: 5141600-8053542 chr16: 6056420-8053542 chr16: 5279421-7736962 0.13 47 Deletion Peak 16q23.1 chr16: 78131135-79628242 chr16: 78131135-79286336 chr16: 78424695-79295468 0.14 48 Deletion Peak 17p12 chr17: 11466949-12461211 chr17: 11872374-11906034 chr17: 10231123-12752622 0.83 49 Deletion Peak 17q24.3 chr17: 68174484-70599305 chr17: 70337175-70590424 chr17: 70549664-70552757 0.30 50 Deletion Peak 18p11.31 chr18: 3277394-4265401 chr18: 3441391-3481373 chr18: 3398771-3729936 0.83 51 Deletion Peak 18q12.2 chr18: 35136370-39061915 chr18: 36781295-37333625 chr18: 35827844-46846953 0.93 52 Deletion Peak 18q21.2 chr18: 48472034-48707815 chr18: 48547928-48660122 chr18: 47049746-78077248 0.94 53 Deletion Peak 18q21.33 chr18: 60645473-61013467 chr18: 60788090-61013467 chr18: 47049746-78077248 0.95 54 Deletion Peak 19p13.3 chr19: 1488247-1660256 chr19: 1488455-1660256 chr19: 1-5957502 0.24 55 Deletion Peak 20p12.1 chr20: 13955189-16350354 chr20: 14416445-15462745 chr20: 14096517-16064189 0.21 56 Deletion Peak 21q11.2 chr21: 15555708-16334057 chr21: 15854887-15919066 chr21: 1-31258004 0.53 57 Deletion Peak 21q21.1 chr21: 23106546-26219369 chr21: 23248652-23494410 chr21: 1-31258004 0.54 58 Deletion Peak 22q13.32 chr22: 48649199-49178363 chr22: 48906309-49158314 chr22: 47983027-51304566 0.78 59 Whole arm 10p NA NA chr10: 1-39254935 0.15 amplification 1 Whole arm 10q NA NA chr16: 1-35335801 0.04 amplification 2 Whole arm 11p NA NA chr16: 38335801-90354753 0.23 amplification 3 Whole arm 11q NA NA chr17: 1-22263006 0.16 amplification 4 Whole arm 12p NA NA chr17: 25263006-81195210 0.23 amplification 5 Whole arm 12q NA NA chr18: 1-15460898 0.15 amplification 6 Whole arm 13q NA NA chr18: 18460898-78077248 0.80 amplification 7 Whole arm 14q NA NA chr19: 1-24681782 0.06 amplification 8 Whole arm 15q NA NA chr19: 27681782-59128983 0.03 amplification 9 Whole arm 16p NA NA chr1: 1-121535434 0.51 amplification 10 Whole arm 16q NA NA chr1: 124535434-249250621 0.45 amplification 11 Whole arm 17p NA NA chr10: 42254935-135534747 0.04 amplification 12 Whole arm 17q NA NA chr20: 1-26369569 0.23 amplification 13 Whole arm 18p NA NA chr20: 29369569-63025520 0.04 amplification 14 Whole arm 18q NA NA chr21: 14288129-48129895 0.02 amplification 15 Whole arm 19p NA NA chr22: 16000000-51304566 0.32 amplification 16 Whole arm 19q NA NA chr2: 1-92326171 0.32 amplification 17 Whole arm 1p NA NA chr2: 95326171-243199373 0.07 amplification 18 Whole arm 1q NA NA chr3: 1-90504854 0.35 amplification 19 Whole arm 20p NA NA chr3: 93504854-198022430 0.64 amplification 20 Whole arm 20q NA NA chr4: 1-49660117 0.93 amplification 21 Whole arm 21q NA NA chr4: 52660117-191154276 0.08 amplification 22 Whole arm 22q NA NA chr11: 1-51644205 0.01 amplification 23 Whole arm 2p NA NA chr5: 1-46405641 0.23 amplification 24 Whole arm 2q NA NA chr5: 49405641-180915260 0.21 amplification 25 Whole arm 3p NA NA chr6: 1-58830166 0.12 amplification 26 Whole arm 3q NA NA chr6: 61830166-171115067 0.20 amplification 27 Whole arm 4p NA NA chr7: 1-58054331 0.02 amplification 28 Whole arm 4q NA NA chr7: 61054331-159138663 0.02 amplification 29 Whole arm 5p NA NA chr8: 1-43838887 0.29 amplification 30 Whole arm 5q NA NA chr8: 46838887-146364022 0.11 amplification 31 Whole arm 6p NA NA chr9: 1-47367679 0.34 amplification 32 Whole arm 6q NA NA chr9: 50367679-141213431 0.28 amplification 33 Whole arm 7p NA NA chr11: 54644205-135006516 0.77 amplification 34 Whole arm 7q NA NA chr12: 1-34856694 0.65 amplification 35 Whole arm 8p NA NA chr12: 37856694-133851895 0.13 amplification 36 Whole arm 8q NA NA chr13: 19000000-115169878 0.51 amplification 37 Whole arm 9p NA NA chr14: 19000000-107349540 0.25 amplification 38 Whole arm 9q NA NA chr15: 20000000-102531392 0.17 amplification 39 Whole arm 10p NA NA chr10: 1-39254935 0.28 deletion 1 Whole arm 10q NA NA chr16: 1-35335801 0.38 deletion 2 Whole arm 11p NA NA chr16: 38335801-90354753 0.25 deletion 3 Whole arm 11q NA NA chr17: 1-22263006 0.31 deletion 4 Whole arm 12p NA NA chr17: 25263006-81195210 0.15 deletion 5 Whole arm 12q NA NA chr18: 1-15460898 0.16 deletion 6 Whole arm 13q NA NA chr18: 18460898-78077248 0.04 deletion 7 Whole arm 14q NA NA chr19: 1-24681782 0.52 deletion 8 Whole arm 15q NA NA chr19: 27681782-59128983 0.65 deletion 9 Whole arm 16p NA NA chr1: 1-121535434 0.09 deletion 10 Whole arm 16q NA NA chr1: 124535434-249250621 0.09 deletion 11 Whole arm 17p NA NA chr10: 42254935-135534747 0.67 deletion 12 Whole arm 17q NA NA chr20: 1-26369569 0.30 deletion 13 Whole arm 18p NA NA chr20: 29369569-63025520 0.84 deletion 14 Whole arm 18q NA NA chr21: 14288129-48129895 0.94 deletion 15 Whole arm 19p NA NA chr22: 16000000-51304566 0.14 deletion 16 Whole arm 19q NA NA chr2: 1-92326171 0.11 deletion 17 Whole arm 1p NA NA chr2: 95326171-243199373 0.41 deletion 18 Whole arm 1q NA NA chr3: 1-90504854 0.15 deletion 19 Whole arm 20p NA NA chr3: 93504854-198022430 0.18 deletion 20 Whole arm 20q NA NA chr4: 1-49660117 0.00 deletion 21 Whole arm 21q NA NA chr4: 52660117-191154276 0.50 deletion 22 Whole arm 22q NA NA chr11: 1-51644205 0.72 deletion 23 Whole arm 2p NA NA chr5: 1-46405641 0.04 deletion 24 Whole arm 2q NA NA chr5: 49405641-180915260 0.04 deletion 25 Whole arm 3p NA NA chr6: 1-58830166 0.21 deletion 26 Whole arm 3q NA NA chr6: 61830166-171115067 0.09 deletion 27 Whole arm 4p NA NA chr7: 1-58054331 0.71 deletion 28 Whole arm 4q NA NA chr7: 61054331-159138663 0.68 deletion 29 Whole arm 5p NA NA chr8: 1-43838887 0.14 deletion 30 Whole arm 5q NA NA chr8: 46838887-146364022 0.26 deletion 31 Whole arm 6p NA NA chr9: 1-47367679 0.13 deletion 32 Whole arm 6q NA NA chr9: 50367679-141213431 0.16 deletion 33 Whole arm 7p NA NA chr11: 54644205-135006516 0.01 deletion 34 Whole arm 7q NA NA chr12: 1-34856694 0.03 deletion 35 Whole arm 8p NA NA chr12: 37856694-133851895 0.59 deletion 36 Whole arm 8q NA NA chr13: 19000000-115169878 0.06 deletion 37 Whole arm 9p NA NA chr14: 19000000-107349540 0.17 deletion 38 Whole arm 9q NA NA chr15: 20000000-102531392 0.20 deletion 39

TABLE 5 Biomarker panel listing the 102 focal genomic regions used to cluster the studied CRC samples in 3 genomic subtypes. The panel of genomic regions consists of 43 focal amplifications, 59 focal deletions. Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits Amplification 1p34.2 chr1: 39144054-44367347 chr1: 42834925-43114106 chr1: 42692914-43456374 Peak 1 (probes 8327:9928) (probes 9441:9533) (probes 9397:9635) Amplification 1q22 chr1: 120494739-199253746 chr1: 155143717-155177826 chr1: 120497533-175439985 Peak 2 (probes 33660:51419) (probes 35410:35412) (probes 33661:42337) Amplification 1q43 chr1: 201615295-249250621 chr1: 242413158-242638099 chr1: 242270003-249250621 Peak 3 (probes 52203:66664) (probes 65295:65368) (probes 65251:66664) Amplification 2q33.1 chr2: 181446594-243199373 chr2: 199603526-199649638 chr2: 199525178-199824262 Peak 4 (probes 121383:140439) (probes 127082:127089) (probes 127052:127139) Amplification 3q29 chr3: 174745992-198022430 chr3: 195922177-195991311 chr3: 174746836-198022430 Peak 5 (probes 195590:202834) (probes 202552:202570) (probes 195591:202834) Amplification 5p15.33 chr5: 1-6418038 chr5: 1-949725 chr5: 1-2807521 Peak 6 (probes 260156:261588) (probes 260156:260170) (probes 260156:260460) Amplification 5p12 chr5: 33430780-50470114 chr5: 43822799-43929095 chr5: 37334807-44266311 Peak 7 (probes 269602:272992) (probes 272538:272572) (probes 270584:272613) Amplification 6p21.1 chr6: 43545080-44164949 chr6: 43765716-44163738 chr6: 36748055-52028937 Peak 8 (probes 323466:323553) (probes 323497:323552) (probes 321584:325929) Amplification 6q23.3 chr6: 135342981-135632150 chr6: 135513416-135593890 chr6: 133418393-138096856 Peak 9 (probes 350621:350776) (probes 350670:350763) (probes 350049:351529) Amplification 7p11.2 chr7: 54949302-55950640 chr7: 55248172-55271747 chr7: 54949902-55955413 Peak 10 (probes 380333:380688) (probes 380546:380547) (probes 380334:380690) Amplification 8p11.23 chr8: 38162916-38237532 chr8: 38165117-38236937 chr8: 34342520-48854434 Peak 11 (probes 417907:417912) (probes 417908:417911) (probes 417738:418611) Amplification 8p11.21 chr8: 41760295-42054539 chr8: 41767516-41796226 chr8: 34342520-48854434 Peak 12 (probes 418156:418183) (probes 418157:418159) (probes 417738:418611) Amplification 8q12.2 chr8: 60847395-62906825 chr8: 61658252-61874896 chr8: 54646329-146364022 Peak 13 (probes 421733:422344) (probes 421947:422037) (probes 420141:444693) Amplification 8q21.13 chr8: 80636493-82552412 chr8: 81853752-81935079 chr8: 54646329-146364022 Peak 14 (probes 427272:427752) (probes 427579:427595) (probes 420141:444693) Amplification 8q22.3 chr8: 101853171-101878037 chr8: 101853464-101876083 chr8: 54646329-146364022 Peak 15 (probes 432850:432855) (probes 432851:432854) (probes 420141:444693) Amplification 8q24.21 chr8: 128574277-128592142 chr8: 128574768-128591041 chr8: 54646329-146364022 Peak 16 (probes 440457:440461) (probes 440458:440460) (probes 420141:444693) Amplification 10q22.3 chr10: 79956009-83248579 chr10: 80445049-80732930 chr10: 77952482-83583616 Peak 17 (probes 504622:505397) (probes 504807:504859) (probes 503919:505484) Amplification 11p15.5 chr11: 2091739-2302637 chr11: 2095340-2301396 chr11: 2095340-2305324 Peak 18 (probes 520960:520971) (probes 520961:520970) (probes 520961:520973) Amplification 11q13.3 chr11: 68746750-69827851 chr11: 69311828-69824706 chr11: 68748468-70760456 Peak 19 (probes 539709:539869) (probes 539796:539868) (probes 539710:540034) Amplification 12p13.32 chr12: 3941807-4552801 chr12: 4257035-4414967 chr12: 1-8970181 Peak 20 (probes 562075:562238) (probes 562162:562219) (probes 561076:563266) Amplification 12p11.22 chr12: 24880798-28477058 chr12: 27800441-27813180 chr12: 25955987-28156868 Peak 21 (probes 567897:568917) (probes 568722:568722) (probes 568181:568838) Amplification 13q12.2 chr13: 28164386-28564331 chr13: 28174614-28222659 chr13: 1-115169878 Peak 22 (probes 600542:600653) (probes 600543:600550) (probes 599000:624834) Amplification 13q22.1 chr13: 73775176-74007122 chr13: 73906681-74004816 chr13: 1-115169878 Peak 23 (probes 612853:612922) (probes 612891:612921) (probes 599000:624834) Amplification 13q34 chr13: 110097815-111753132 chr13: 110614601-110852082 chr13: 1-115169878 Peak 24 (probes 624037:624356) (probes 624207:624235) (probes 599000:624834) Amplification 15q26.1 chr15: 84648780-102531392 chr15: 90811423-90958538 chr15: 90086447-91895585 Peak 25 (probes 669559:675028) (probes 671504:671507) (probes 671145:671795) Amplification 16p11.2 chr16: 30548665-30684980 chr16: 30549334-30682578 chr16: 28556705-46663588 Peak 26 (probes 681497:681499) (probes 681498:681498) (probes 681456:681707) Amplification 16q12.1 chr16: 52243935-52652774 chr16: 52383686-52652198 chr16: 51078632-53117566 Peak 27 (probes 683896:684007) (probes 683905:684006) (probes 683397:684118) Amplification 17q11.2 chr17: 27339261-27528113 chr17: 27339592-27419750 chr17: 20042949-40168023 Peak 28 (probes 701849:701907) (probes 701850:701866) (probes 701549:704344) Amplification 17q12 chr17: 37747533-38052599 chr17: 37950674-38031986 chr17: 20042949-40168023 Peak 29 (probes 703891:703930) (probes 703917:703929) (probes 701549:704344) Amplification 17q23.2 chr17: 58400463-58674819 chr17: 58400997-58532661 chr17: 57045336-62714320 Peak 30 (probes 708991:709072) (probes 708992:709031) (probes 708646:710280) Amplification 17q24.2 chr17: 65638523-65873408 chr17: 65649475-65769071 chr17: 63042470-68655121 Peak 31 (probes 710976:711074) (probes 710978:711037) (probes 710378:712109) Amplification 17q25.3 chr17: 77601682-77857881 chr17: 77766436-77856811 chr17: 75845339-81195210 Peak 32 (probes 714127:714155) (probes 714137:714154) (probes 713778:714413) Amplification 18q11.2 chr18: 19517253-20155059 chr18: 19525020-20154578 chr18: 19243919-21268418 Peak 33 (probes 718275:718278) (probes 718276:718277) (probes 718239:718447) Amplification 18q21.1 chr18: 46041609-46930382 chr18: 46474762-46604295 chr18: 46043163-46624631 Peak 34 (probes 725325:725688) (probes 725462:725478) (probes 725326:725481) Amplification 19q13.11 chr19: 32439834-33021877 chr19: 32966965-32988344 chr19: 19939350-41312227 Peak 35 (probes 739770:739825) (probes 739799:739805) (probes 739769:742785) Amplification 19q13.2 chr19: 39844313-40357920 chr19: 39848086-40009185 chr19: 19939350-41312227 Peak 36 (probes 742339:742488) (probes 742340:742365) (probes 739769:742785) Amplification 20p12.3 chr20: 5376354-5742957 chr20: 5379141-5737687 chr20: 5156552-5961498 Peak 37 (probes 749386:749394) (probes 749387:749393) (probes 749320:749400) Amplification 20p12.1 chr20: 16140291-16967195 chr20: 16488303-16962609 chr20: 16146669-16970141 Peak 38 (probes 751931:752121) (probes 751982:752120) (probes 751932:752123) Amplification 20p11.22 chr20: 22058560-22353663 chr20: 22063756-22350551 chr20: 20938975-24286806 Peak 39 (probes 753204:753212) (probes 753205:753211) (probes 753103:753480) Amplification 20q11.21 chr20: 29981165-30284236 chr20: 30158807-30231055 chr20: 24375411-63025520 Peak 40 (probes 753711:753769) (probes 753729:753748) (probes 753519:762719) Amplification 20q13.12 chr20: 42534268-43281676 chr20: 42537604-42773258 chr20: 24375411-63025520 Peak 41 (probes 756743:756930) (probes 756744:756753) (probes 753519:762719) Amplification 20q13.2 chr20: 52240629-52852159 chr20: 52246659-52447690 chr20: 24375411-63025520 Peak 42 (probes 759885:759989) (probes 759886:759947) (probes 753519:762719) Amplification 20q13.32 chr20: 56110288-57258354 chr20: 57000076-57085518 chr20: 24375411-63025520 Peak 43 (probes 760955:761384) (probes 761307:761325) (probes 753519:762719) Deletion Peak 1 1p36.31 chr1: 4843384-6053964 chr1: 5646446-6050774 chr1: 1-37080378 (probes 343:539) (probes 537:538) (probes 1:7694) Deletion Peak 2 1p36.11 chr1: 26898389-27219375 chr1: 27139248-27185402 chr1: 1-37080378 (probes 5577:5639) (probes 5629:5630) (probes 1:7694) Deletion Peak 3 1p33 chr1: 49187432-50544677 chr1: 48847112-50490440 chr1: 49196205-51396500 (probes 11383:11605) (probes 11319:11598) (probes 11385:11801) Deletion Peak 4 1p31.1 chr1: 68959091-82269682 chr1: 79308665-79566142 chr1: 54944113-149961894 (probes 17617:22019) (probes 20993:20994) (probes 12746:33663) Deletion Peak 5 1p21.1 chr1: 102460262-107618224 chr1: 104041213-104355050 chr1: 54944113-149961894 (probes 28724:30035) (probes 29059:29060) (probes 12746:33663) Deletion Peak 6 2p25.3 chr2: 1-4752017 chr2: 1-488785 chr2: 1-5260278 (probes 66665:67509) (probes 66665:66665) (probes 66665:67543) Deletion Peak 7 2p21 chr2: 42587649-44009118 chr2: 43440855-43455807 chr2: 43159857-43470966 (probes 79800:80265) (probes 80094:80097) (probes 79991:80104) Deletion Peak 8 2q23.1 chr2: 147341956-149499455 chr2: 148437688-148750846 chr2: 148444810-148756213 (probes 110935:111344) (probes 111211:111212) (probes 111212:111213) Deletion Peak 9 2q37.3 chr2: 240321205-243199373 chr2: 240940975-241060875 chr2: 240589192-241997730 (probes 139897:140439) (probes 140116:140117) (probes 139997:140352) Deletion Peak 10 3p26.3 chr3: 1-8350135 chr3: 1-2251569 chr3: 1-9456413 (probes 140440:142376) (probes 140440:140440) (probes 140440:142660) Deletion Peak 11 3p14.2 chr3: 58946448-61555632 chr3: 59692189-61457375 chr3: 59692189-61460946 (probes 159123:159363) (probes 159317:159339) (probes 159317:159341) Deletion Peak 12 3p13 chr3: 70014100-71250049 chr3: 70976616-71182883 chr3: 70977475-71315576 (probes 162276:162774) (probes 162708:162756) (probes 162709:162793) Deletion Peak 13 3q26.31 chr3: 173995229-175766885 chr3: 174575326-175766885 chr3: 174646449-174998725 (probes 195434:195620) (probes 195555:195620) (probes 195574:195593) Deletion Peak 14 4p16.2 chr4: 1-9787265 chr4: 5915497-5925651 chr4: 1-11455571 (probes 202835:205184) (probes 204117:204118) (probes 202835:205810) Deletion Peak 15 4q22.1 chr4: 91143530-93226628 chr4: 91046982-92557520 chr4: 91103554-92561908 (probes 229840:230295) (probes 229814:230049) (probes 229834:230051) Deletion Peak 16 4q25 chr4: 109046573-109544048 chr4: 109451604-109544048 chr4: 109489936-109535239 (probes 235677:235829) (probes 235801:235829) (probes 235811:235826) Deletion Peak 17 4q31.3 chr4: 152679194-153694102 chr4: 153232273-153473069 chr4: 152233433-191154276 (probes 249686:250016) (probes 249909:249977) (probes 249594:260155) Deletion Peak 18 4q32.1 chr4: 156135292-162306004 chr4: 159683040-159830757 chr4: 152233433-191154276 (probes 250770:252941) (probes 252055:252100) (probes 249594:260155) Deletion Peak 19 4q35.1 chr4: 184432080-185262191 chr4: 184545375-185154488 chr4: 152233433-191154276 (probes 259152:259216) (probes 259180:259181) (probes 249594:260155) Deletion Peak 20 5p15.33 chr5: 1-2750686 chr5: 1368344-2252637 chr5: 1-3864653 (probes 260156:260443) (probes 260268:260279) (probes 260156:260838) Deletion Peak 21 5q12.1 chr5: 58263825-59784640 chr5: 58263825-59784640 chr5: 50968806-135478060 (probes 275334:275642) (probes 275334:275642) (probes 273162:297537) Deletion Peak 22 5q22.2 chr5: 111312546-112362638 chr5: 111747052-111761475 chr5: 50968806-135478060 (probes 290226:290685) (probes 290365:290367) (probes 273162:297537) Deletion Peak 23 6p25.3 chr6: 1613114-2256643 chr6: 1621843-2256643 chr6: 1626114-2752758 (probes 311779:311876) (probes 311784:311876) (probes 311786:312043) Deletion Peak 24 6p22.2 chr6: 25926929-26025173 chr6: 25932794-26025173 chr6: 25933563-26346501 (probes 319619:319631) (probes 319620:319631) (probes 319621:319690) Deletion Peak 25 6q21 chr6: 91006553-129206367 chr6: 111544567-112706964 chr6: 108785353-116683959 (probes 337170:348684) (probes 343210:343577) (probes 342315:344882) Deletion Peak 26 6q26 chr6: 161540781-163179430 chr6: 161540781-163179430 chr6: 160448048-171115067 (probes 359016:359155) (probes 359016:359155) (probes 358753:361110) Deletion Peak 27 7q31.1 chr7: 109590674-111367757 chr7: 110232248-111358792 chr7: 110595801-110618403 (probes 392698:393070) (probes 392932:393069) (probes 393001:393002) Deletion Peak 28 8p23.3 chr8: 1-1449850 chr8: 1-623109 chr8: 1-10801317 (probes 408036:408314) (probes 408036:408036) (probes 408036:410838) Deletion Peak 29 8p21.3 chr8: 13423967-26607015 chr8: 21547484-21647267 chr8: 11646511-25738962 (probes 411497:416107) (probes 414395:414425) (probes 411142:415781) Deletion Peak 30 8p12 chr8: 33445578-37452445 chr8: 34944675-36494184 chr8: 35186331-35207233 (probes 417581:417886) (probes 417838:417861) (probes 417850:417851) Deletion Peak 31 8q11.1 chr8: 42874387-48101823 chr8: 42931769-48061147 chr8: 42932439-48062091 (probes 418403:418427) (probes 418413:418414) (probes 418414:418415) Deletion Peak 32 9p21.3 chr9: 21558582-22452906 chr9: 21995318-22021004 chr9: 21711940-22331169 (probes 452306:452602) (probes 452487:452491) (probes 452378:452557) Deletion Peak 33 10p15.3 chr10: 1-855610 chr10: 1-418075 chr10: 1-2055670 (probes 482107:482163) (probes 482107:482107) (probes 482107:482391) Deletion Peak 34 10q21.1 chr10: 51561927-53481136 chr10: 51561927-54065263 chr10: 50763189-54253314 (probes 495717:495904) (probes 495717:496053) (probes 495699:496079) Deletion Peak 35 10q23.31 chr10: 89502327-90051809 chr10: 89574482-89607380 chr10: 83248858-135534747 (probes 507191:507378) (probes 507201:507204) (probes 505400:520735) Deletion Peak 36 10q25.2 chr10: 114197471-115353755 chr10: 114708532-114929210 chr10: 83248858-135534747 (probes 515003:515382) (probes 515200:515269) (probes 505400:520735) Deletion Peak 37 10q26.3 chr10: 133107199-135534747 chr10: 135221096-135534747 chr10: 83248858-135534747 (probes 520190:520735) (probes 520735:520735) (probes 505400:520735) Deletion Peak 38 11q22.3 chr11: 102958343-135006516 chr11: 108251085-108350263 chr11: 108179920-108470348 (probes 551128:561075) (probes 552798:552832) (probes 552783:552882) Deletion Peak 39 12p13.2 chr12: 12412186-13039757 chr12: 12525464-12721981 chr12: 11739866-13828006 (probes 564161:564352) (probes 564230:564257) (probes 563986:564574) Deletion Peak 40 12q21.2 chr12: 75602135-79819184 chr12: 76423769-76523220 chr12: 75648890-78593389 (probes 581594:583083) (probes 581862:581874) (probes 581614:582689) Deletion Peak 41 12q24.33 chr12: 125048064-133851895 chr12: 131256822-131362341 chr12: 125246979-133851895 (probes 597584:598999) (probes 598784:598790) (probes 597646:598999) Deletion Peak 42 14q24.1 chr14: 68280014-69351476 chr14: 68284712-68948164 chr14: 68343659-68985929 (probes 640423:640650) (probes 640425:640565) (probes 640446:640573) Deletion Peak 43 14q32.11 chr14: 78347564-107349540 chr14: 90999841-91286309 chr14: 90170502-92315681 (probes 643482:652331) (probes 647605:647693) (probes 647318:648035) Deletion Peak 44 15q11.2 chr15: 25436434-25466900 chr15: 25438412-25459423 chr15: 1-58781038 (probes 652975:652987) (probes 652978:652984) (probes 652332:661726) Deletion Peak 45 15q21.1 chr15: 44850582-45321541 chr15: 44851811-45052539 chr15: 1-58781038 (probes 657156:657216) (probes 657157:657198) (probes 652332:661726) Deletion Peak 46 15q22.33 chr15: 67053712-67697647 chr15: 67337017-67551787 chr15: 67245914-67753643 (probes 664346:664503) (probes 664432:664448) (probes 664397:664514) Deletion Peak 47 16p13.3 chr16: 5141600-8053542 chr16: 6056420-8053542 chr16: 5279421-7736962 (probes 676035:676388) (probes 676266:676388) (probes 676069:676383) Deletion Peak 48 16q23.1 chr16: 78131135-79628242 chr16: 78131135-79286336 chr16: 78424695-79295468 (probes 692486:692917) (probes 692486:692739) (probes 692585:692741) Deletion Peak 49 17p12 chr17: 11466949-12461211 chr17: 11872374-11906034 chr17: 10231123-12752622 (probes 699252:699560) (probes 699350:699356) (probes 698870:699686) Deletion Peak 50 17q24.3 chr17: 68174484-70599305 chr17: 70337175-70590424 chr17: 70549664-70552757 (probes 711906:712713) (probes 712684:712712) (probes 712699:712700) Deletion Peak 51 18p11.31 chr18: 3277394-4265401 chr18: 3441391-3481373 chr18: 3398771-3729936 (probes 715148:715497) (probes 715189:715190) (probes 715178:715261) Deletion Peak 52 18q12.2 chr18: 35136370-39061915 chr18: 36781295-37333625 chr18: 35827844-46846953 (probes 722194:723278) (probes 722627:722752) (probes 722377:725639) Deletion Peak 53 18q21.2 chr18: 48472034-48707815 chr18: 48547928-48660122 chr18: 47049746-78077248 (probes 725965:726002) (probes 725987:725988) (probes 725727:734875) Deletion Peak 54 18q21.33 chr18: 60645473-61013467 chr18: 60788090-61013467 chr18: 47049746-78077248 (probes 730126:730222) (probes 730167:730222) (probes 725727:734875) Deletion Peak 55 19p13.3 chr19: 1488247-1660256 chr19: 1488455-1660256 chr19: 1-5957502 (probes 735045:735049) (probes 735046:735049) (probes 734876:735790) Deletion Peak 56 20p12.1 chr20: 13955189-16350354 chr20: 14416445-15462745 chr20: 14096517-16064189 (probes 751741:751931) (probes 751773:751774) (probes 751766:751890) Deletion Peak 57 21q11.2 chr21: 15555708-16334057 chr21: 15854887-15919066 chr21: 1-31258004 (probes 762725:762981) (probes 762833:762869) (probes 762720:767383) Deletion Peak 58 21q21.1 chr21: 23106546-26219369 chr21: 23248652-23494410 chr21: 1-31258004 (probes 765049:765801) (probes 765109:765118) (probes 762720:767383) Deletion Peak 59 22q13.32 chr22: 48649199-49178363 chr22: 48906309-49158314 chr22: 47983027-51304566 (probes 781080:781144) (probes 781137:781140) (probes 780856:781177)

TABLE 6 Tier 1 selection of genomic markers used in recursive partitioning from all 180 regions. Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits Deletion Peak 56 20p12.1 chr20: 13955189-16350354 chr20: 14416445-15462745 chr20: 14096517-16064189 Deletion Peak 11 3p14.2 chr3: 58946448-61555632 chr3: 59692189-61457375 chr3: 59692189-61460946 Deletion Peak 26 6q26 chr6: 161540781-163179430 chr6: 161540781-163179430 chr6: 160448048-171115067 Amplification Peak 20p12.3 chr20: 5376354-5742957 chr20: 5379141-5737687 chr20: 5156552-5961498 37 Deletion Peak 38 11q22.3 chr11: 102958343-135006516 chr11: 108251085-108350263 chr11: 108179920-108470348 Deletion Peak 52 18q12.2 chr18: 35136370-39061915 chr18: 36781295-37333625 chr18: 35827844-46846953 Amplification Peak 20q13.12 chr20: 42534268-43281676 chr20: 42537604-42773258 chr20: 24375411-63025520 41 Deletion Peak 34 10q21.1 chr10: 51561927-53481136 chr10: 51561927-54065263 chr10: 50763189-54253314 Whole arm 20p NA NA chr20: 1-26369569 amplification 20 Deletion Peak 25 6q21 chr6: 91006553-129206367 chr6: 111544567-112706964 chr6: 108785353-116683959 Amplification Peak 8p11.21 chr8: 41760295-42054539 chr8: 41767516-41796226 chr8: 34342520-48854434 12 Deletion Peak 40 12q21.2 chr12: 75602135-79819184 chr12: 76423769-76523220 chr12: 75648890-78593389 Deletion Peak 28 8p23.3 chr8: 1-1449850 chr8: 1-623109 chr8: 1-10801317 Deletion Peak 15 4q22.1 chr4: 91143530-93226628 chr4: 91046982-92557520 chr4: 91103554-92561908 Amplification Peak 17q11.2 chr17: 27339261-27528113 chr17: 27339592-27419750 chr17: 20042949-40168023 28 Whole arm 10q NA NA chr10: 42254935-135534747 deletion 2 Amplification Peak 20p12.1 chr20: 16140291-16967195 chr20: 16488303-16962609 chr20: 16146669-16970141 38 Whole arm 5q NA NA chr5: 49405641-180915260 deletion 31 Deletion Peak 36 10q25.2 chr10: 114197471-115353755 chr10: 114708532-114929210 chr10: 83248858-135534747 Deletion Peak 23 6p25.3 chr6: 1613114-2256643 chr6: 1621843-2256643 chr6: 1626114-2752758 Deletion Peak 59 22q13.32 chr22: 48649199-49178363 chr22: 48906309-49158314 chr22: 47983027-51304566 Amplification Peak 17q12 chr17: 37747533-38052599 chr17: 37950674-38031986 chr17: 20042949-40168023 29 Deletion Peak 24 6p22.2 chr6: 25926929-26025173 chr6: 25932794-26025173 chr6: 25933563-26346501 Amplification Peak 20q13.32 chr20: 56110288-57258354 chr20: 57000076-57085518 chr20: 24375411-63025520 43 Deletion Peak 22 5q22.2 chr5: 111312546-112362638 chr5: 111747052-111761475 chr5: 50968806-135478060 Deletion Peak 35 10q23.31 chr10: 89502327-90051809 chr10: 89574482-89607380 chr10: 83248858-135534747 Deletion Peak 58 21q21.1 chr21: 23106546-26219369 chr21: 23248652-23494410 chr21: 1-31258004 Deletion Peak 57 21q11.2 chr21: 15555708-16334057 chr21: 15854887-15919066 chr21: 1-31258004 Whole arm 18q NA NA chr18: 18460898-78077248 deletion 15 Deletion Peak 17 4q31.3 chr4: 152679194-153694102 chr4: 153232273-153473069 chr4: 152233433-191154276 Deletion Peak 18 4q32.1 chr4: 156135292-162306004 chr4: 159683040-159830757 chr4: 152233433-191154276 Deletion Peak 53 18q21.2 chr18: 48472034-48707815 chr18: 48547928-48660122 chr18: 47049746-78077248 Whole arm 21q NA NA chr21: 14288129-48129895 deletion 22 Whole arm 9p NA NA chr9: 1-47367679 deletion 38 Amplification Peak 20q13.2 chr20: 52240629-52852159 chr20: 52246659-52447690 chr20: 24375411-63025520 42 Whole arm 22q NA NA chr22: 16000000-51304566 deletion 23

TABLE 7 Tier 2 selection of genomic markers used in recursive partitioning from all 180 regions. Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits Amplification Peak 8q24.21 chr8: 128574277-128592142 chr8: 128574768-128591041 chr8: 54646329-146364022 16 Amplification Peak 17q24.2 chr17: 65638523-65873408 chr17: 65649475-65769071 chr17: 63042470-68655121 31 Deletion Peak 39 12p13.2 chr12: 12412186-13039757 chr12: 12525464-12721981 chr12: 11739866-13828006 Deletion Peak 10 3p26.3 chr3: 1-8350135 chr3: 1-2251569 chr3: 1-9456413 Whole arm 17p NA NA chr17: 1-22263006 deletion 12 Deletion Peak 55 19p13.3 chr19: 1488247-1660256 chr19: 1488455-1660256 chr19: 1-5957502 Amplification Peak 3 1q43 chr1: 201615295-249250621 chr1: 242413158-242638099 chr1: 242270003-249250621 Whole arm 14q NA NA chr14: 19000000-107349540 deletion 8 Deletion Peak 50 17q24.3 chr17: 68174484-70599305 chr17: 70337175-70590424 chr17: 70549664-70552757 Whole arm 18p NA NA chr18: 1-15460898 deletion 14 Amplification Peak 5 3q29 chr3: 174745992-198022430 chr3: 195922177-195991311 chr3: 174746836-198022430 Whole arm 7p NA NA chr7: 1-58054331 amplification 34 Amplification Peak 13q12.2 chr13: 28164386-28564331 chr13: 28174614-28222659 chr13: 1-115169878 22 Deletion Peak 43 14q32.11 chr14: 78347564-107349540 chr14: 90999841-91286309 chr14: 90170502-92315681 Amplification Peak 20p11.22 chr20: 22058560-22353663 chr20: 22063756-22350551 chr20: 20938975-24286806 39 Deletion Peak 4 1p31.1 chr1: 68959091-82269682 chr1: 79308665-79566142 chr1: 54944113-149961894 Deletion Peak 42 14q24.1 chr14: 68280014-69351476 chr14: 68284712-68948164 chr14: 68343659-68985929 Deletion Peak 51 18p11.31 chr18: 3277394-4265401 chr18: 3441391-3481373 chr18: 3398771-3729936 Deletion Peak 19 4q35.1 chr4: 184432080-185262191 chr4: 184545375-185154488 chr4: 152233433-191154276 Deletion Peak 31 8q11.1 chr8: 42874387-48101823 chr8: 42931769-48061147 chr8: 42932439-48062091 Whole arm 11q NA NA chr11: 54644205-135006516 deletion 4 Deletion Peak 30 8p12 chr8: 33445578-37452445 chr8: 34944675-36494184 chr8: 35186331-35207233 Amplification Peak 17q23.2 chr17: 58400463-58674819 chr17: 58400997-58532661 chr17: 57045336-62714320 30 Whole arm 4p NA NA chr4: 1-49660117 deletion 28 Amplification Peak 8p11.23 chr8: 38162916-38237532 chr8: 38165117-38236937 chr8: 34342520-48854434 11 Whole arm 6p NA NA chr6: 1-58830166 deletion 32 Amplification Peak 8q22.3 chr8: 101853171-101878037 chr8: 101853464-101876083 chr8: 54646329-146364022 15 Whole arm 6q NA NA chr6: 61830166-171115067 deletion 33 Whole arm 15q NA NA chr15: 20000000-102531392 deletion 9 Deletion Peak 12 3p13 chr3: 70014100-71250049 chr3: 70976616-71182883 chr3: 70977475-71315576 Amplification Peak 8q12.2 chr8: 60847395-62906825 chr8: 61658252-61874896 chr8: 54646329-146364022 13 Deletion Peak 21 5q12.1 chr5: 58263825-59784640 chr5: 58263825-59784640 chr5: 50968806-135478060 Deletion Peak 5 1p21.1 chr1: 102460262-107618224 chr1: 104041213-104355050 chr1: 54944113-149961894 Deletion Peak 37 10q26.3 chr10: 133107199-135534747 chr10: 135221096-135534747 chr10: 83248858-135534747 Whole arm 20q NA NA chr20: 29369569-63025520 amplification 21 Amplification Peak 8 6p21.1 chr6: 43545080-44164949 chr6: 43765716-44163738 chr6: 36748055-52028937 Whole arm 10p NA NA chr10: 1-39254935 deletion 1 Whole arm 9q NA NA chr9: 50367679-141213431 amplification 39 Deletion Peak 3 1p33 chr1: 49187432-50544677 chr1: 48847112-50490440 chr1: 49196205-51396500 Deletion Peak 49 17p12 chr17: 11466949-12461211 chr17: 11872374-11906034 chr17: 10231123-12752622 Deletion Peak 46 15q22.33 chr15: 67053712-67697647 chr15: 67337017-67551787 chr15: 67245914-67753643 Whole arm 8q NA NA chr8: 46838887-146364022 amplification 37 Deletion Peak 16 4q25 chr4: 109046573-109544048 chr4: 109451604-109544048 chr4: 109489936-109535239 Whole arm 17q NA NA chr17: 25263006-81195210 deletion 13 Amplification Peak 8q21.13 chr8: 80636493-82552412 chr8: 81853752-81935079 chr8: 54646329-146364022 14 Whole arm 4q NA NA chr4: 52660117-191154276 deletion 29 Deletion Peak 54 18q21.33 chr18: 60645473-61013467 chr18: 60788090-61013467 chr18: 47049746-78077248 Amplification Peak 20q11.21 chr20: 29981165-30284236 chr20: 30158807-30231055 chr20: 24375411-63025520 40

TABLE 8 Tier 3 selection of genomic markers used in recursive partitioning from all 180 regions. Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits Amplification Peak 11q13.3 chr11: 68746750-69827851 chr11: 69311828-69824706 chr11: 68748468-70760456 19 Whole arm 11q NA NA chr11: 54644205-135006516 amplification 4 Whole arm deletion 3q NA NA chr3: 93504854-198022430 27 Whole arm deletion 9q NA NA chr9: 50367679-141213431 39 Whole arm 4q NA NA chr4: 52660117-191154276 amplification 29 Amplification Peak 11p15.5 chr11: 2091739-2302637 chr11: 2095340-2301396 chr11: 2095340-2305324 18 Deletion Peak 48 16q23.1 chr16: 78131135-79628242 chr16: 78131135-79286336 chr16: 78424695-79295468 Whole arm deletion 8q NA NA chr8: 46838887-146364022 37 Amplification Peak 16q12.1 chr16: 52243935-52652774 chr16: 52383686-52652198 chr16: 51078632-53117566 27 Amplification Peak 19q13.2 chr19: 39844313-40357920 chr19: 39848086-40009185 chr19: 19939350-41312227 36 Amplification Peak 4 2q33.1 chr2: 181446594-243199373 chr2: 199603526-199649638 chr2: 199525178-199824262 Amplification Peak 13q34 chr13: 110097815-111753132 chr13: 110614601-110852082 chr13: 1-115169878 24 Whole arm 16q NA NA chr16: 38335801-90354753 amplification 11 Whole arm 11p NA NA chr11: 1-51644205 amplification 3 Whole arm deletion 3p NA NA chr3: 1-90504854 26 Deletion Peak 32 9p21.3 chr9: 21558582-22452906 chr9: 21995318-22021004 chr9: 21711940-22331169 Deletion Peak 47 16p13.3 chr16: 5141600-8053542 chr16: 6056420-8053542 chr16: 5279421-7736962 Whole arm 6p NA NA chr6: 1-58830166 amplification 32 Amplification Peak 19q13.11 chr19: 32439834-33021877 chr19: 32966965-32988344 chr19: 19939350-41312227 35 Whole arm deletion 20p NA NA chr20: 1-26369569 20 Deletion Peak 20 5p15.33 chr5: 1-2750686 chr5: 1368344-2252637 chr5: 1-3864653 Deletion Peak 1 1p36.31 chr1: 4843384-6053964 chr1: 5646446-6050774 chr1: 1-37080378 Whole arm 5p NA NA chr5: 1-46405641 amplification 30 Amplification Peak 12p11.22 chr12: 24880798-28477058 chr12: 27800441-27813180 chr12: 25955987-28156868 21 Whole arm 19p NA NA chr19: 1-24681782 amplification 16 Amplification Peak 2 1q22 chr1: 120494739-199253746 chr1: 155143717-155177826 chr1: 120497533-175439985 Whole arm deletion 1q NA NA chr1: 124535434-249250621 19 Deletion Peak 41 12q24.33 chr12: 125048064-133851895 chr12: 131256822-131362341 chr12: 125246979-133851895 Deletion Peak 13 3q26.31 chr3: 173995229-175766885 chr3: 174575326-175766885 chr3: 174646449-174998725 Whole arm deletion 6 12q NA NA chr12: 37856694-133851895 Whole arm 3q NA NA chr3: 93504854-198022430 amplification 27 Whole arm deletion 19q NA NA chr19: 27681782-59128983 17 Whole arm 1q NA NA chr1: 124535434-249250621 amplification 19 Amplification Peak 17q25.3 chr17: 77601682-77857881 chr17: 77766436-77856811 chr17: 75845339-81195210 32 Whole arm 8p NA NA chr8: 1-43838887 amplification 36 Amplification Peak 16p11.2 chr16: 30548665-30684980 chr16: 30549334-30682578 chr16: 28556705-46663588 26 Whole arm deletion 1p NA NA chr1: 1-121535434 18 Whole arm 13q NA NA chr13: 19000000-115169878 amplification 7 Whole arm 17q NA NA chr17: 25263006-81195210 amplification 13 Deletion Peak 44 15q11.2 chr15: 25436434-25466900 chr15: 25438412-25459423 chr15: 1-58781038 Whole arm 1p NA NA chr1: 1-121535434 amplification 18 Deletion Peak 33 10p15.3 chr10: 1-855610 chr10: 1-418075 chr10: 1-2055670 Deletion Peak 45 15q21.1 chr15: 44850582-45321541 chr15: 44851811-45052539 chr15: 1-58781038 Whole arm deletion 5p NA NA chr5: 1-46405641 30 Deletion Peak 7 2p21 chr2: 42587649-44009118 chr2: 43440855-43455807 chr2: 43159857-43470966 Whole arm deletion 8p NA NA chr8: 1-43838887 36 Deletion Peak 2 1p36.11 chr1: 26898389-27219375 chr1: 27139248-27185402 chr1: 1-37080378 Deletion Peak 14 4p16.2 chr4: 1-9787265 chr4: 5915497-5925651 chr4: 1-11455571 Amplification Peak 13q22.1 chr13: 73775176-74007122 chr13: 73906681-74004816 chr13: 1-115169878 23 Deletion Peak 29 8p21.3 chr8: 13423967-26607015 chr8: 21547484-21647267 chr8: 11646511-25738962 Whole arm deletion 3 11p NA NA chr11: 1-51644205

TABLE 9 Tier 4 selection of genomic markers used in recursive partitioning from all 180 regions. Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits Whole arm 2p NA NA chr2: 1-92326171 amplification 24 Whole arm 2q NA NA chr2: 95326171-243199373 amplification 25 Whole arm 3p NA NA chr3: 1-90504854 amplification 26 Whole arm 4p NA NA chr4: 1-49660117 amplification 28 Whole arm 5q NA NA chr5: 49405641-180915260 amplification 31 Whole arm 6q NA NA chr6: 61830166-171115067 amplification 33 Whole arm 7q NA NA chr7: 61054331-159138663 amplification 35 Whole arm 9p NA NA chr9: 1-47367679 amplification 38 Whole arm 10p NA NA chr10: 1-39254935 amplification 1 Whole arm 10q NA NA chr10: 42254935-135534747 amplification 2 Whole arm 12p NA NA chr12: 1-34856694 amplification 5 Whole arm 12q NA NA chr12: 37856694-133851895 amplification 6 Whole arm 14q NA NA chr14: 19000000-107349540 amplification 8 Whole arm 15q NA NA chr15: 20000000-102531392 amplification 9 Whole arm 16p NA NA chr16: 1-35335801 amplification 10 Whole arm 17p NA NA chr17: 1-22263006 amplification 12 Whole arm 18p NA NA chr18: 1-15460898 amplification 14 Whole arm 18q NA NA chr18: 18460898-78077248 amplification 15 Whole arm 19q NA NA chr19: 27681782-59128983 amplification 17 Whole arm 21q NA NA chr21: 14288129-48129895 amplification 22 Whole arm 22q NA NA chr22: 16000000-51304566 amplification 23 Whole arm deletion 2p NA NA chr2: 1-92326171 24 Whole arm deletion 2q NA NA chr2: 95326171-243199373 25 Whole arm deletion 7p NA NA chr7: 1-58054331 34 Whole arm deletion 7q NA NA chr7: 61054331-159138663 35 Whole arm deletion 5 12p NA NA chr12: 1-34856694 Whole arm deletion 7 13q NA NA chr13: 19000000-115169878 Whole arm deletion 16p NA NA chr16: 1-35335801 10 Whole arm deletion 16q NA NA chr16: 38335801-90354753 11 Whole arm deletion 19p NA NA chr19: 1-24681782 16 Whole arm deletion 20q NA NA chr20: 29369569-63025520 21 Amplification Peak 1 1p34.2 chr1: 39144054-44367347 chr1: 42834925-43114106 chr1: 42692914-43456374 Amplification Peak 6 5p15.33 chr5: 1-6418038 chr5: 1-949725 chr5: 1-2807521 Amplification Peak 7 5p12 chr5: 33430780-50470114 chr5: 43822799-43929095 chr5: 37334807-44266311 Amplification Peak 9 6q23.3 chr6: 135342981-135632150 chr6: 135513416-135593890 chr6: 133418393-138096856 Amplification Peak 7p11.2 chr7: 54949302-55950640 chr7: 55248172-55271747 chr7: 54949902-55955413 10 Amplification Peak 10q22.3 chr10: 79956009-83248579 chr10: 80445049-80732930 chr10: 77952482-83583616 17 Amplification Peak 12p13.32 chr12: 3941807-4552801 chr12: 4257035-4414967 chr12: 1-8970181 20 Amplification Peak 15q26.1 chr15: 84648780-102531392 chr15: 90811423-90958538 chr15: 90086447-91895585 25 Amplification Peak 18q11.2 chr18: 19517253-20155059 chr18: 19525020-20154578 chr18: 19243919-21268418 33 Amplification Peak 18q21.1 chr18: 46041609-46930382 chr18: 46474762-46604295 chr18: 46043163-46624631 34 Deletion Peak 6 2p25.3 chr2: 1-4752017 chr2: 1-488785 chr2: 1-5260278 Deletion Peak 8 2q23.1 chr2: 147341956-149499455 chr2: 148437688-148750846 chr2: 148444810-148756213 Deletion Peak 9 2q37.3 chr2: 240321205-243199373 chr2: 240940975-241060875 chr2: 240589192-241997730 Deletion Peak 27 7q31.1 chr7: 109590674-111367757 chr7: 110232248-111358792 chr7: 110595801-110618403

TABLE 10 Tier 1 selection of genomic markers used in recursive partitioning from the 102 focal regions. Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits Amplification Peak 2 1q22 chr1: 120494739-199253746 chr1: 155143717-155177826 chr1: 120497533-175439985 Deletion Peak 43 14q32.11 chr14: 78347564-107349540 chr14: 90999841-91286309 chr14: 90170502-92315681 Amplification Peak 20p11.22 chr20: 22058560-22353663 chr20: 22063756-22350551 chr20: 20938975-24286806 39 Amplification Peak 20p12.3 chr20: 5376354-5742957 chr20: 5379141-5737687 chr20: 5156552-5961498 37 Deletion Peak 12 3p13 chr3: 70014100-71250049 chr3: 70976616-71182883 chr3: 70977475-71315576 Amplification Peak 20q13.12 chr20: 42534268-43281676 chr20: 42537604-42773258 chr20: 24375411-63025520 41 Deletion Peak 25 6q21 chr6: 91006553-129206367 chr6: 111544567-112706964 chr6: 108785353-116683959 Amplification Peak 8q22.3 chr8: 101853171-101878037 chr8: 101853464-101876083 chr8: 54646329-146364022 15 Amplification Peak 20p12.1 chr20: 16140291-16967195 chr20: 16488303-16962609 chr20: 16146669-16970141 38 Deletion Peak 28 8p23.3 chr8: 1-1449850 chr8: 1-623109 chr8: 1-10801317 Amplification Peak 8p11.21 chr8: 41760295-42054539 chr8: 41767516-41796226 chr8: 34342520-48854434 12 Deletion Peak 40 12q21.2 chr12: 75602135-79819184 chr12: 76423769-76523220 chr12: 75648890-78593389 Deletion Peak 26 6q26 chr6: 161540781-163179430 chr6: 161540781-163179430 chr6: 160448048-171115067 Deletion Peak 34 10q21.1 chr10: 51561927-53481136 chr10: 51561927-54065263 chr10: 50763189-54253314 Deletion Peak 46 15q22.33 chr15: 67053712-67697647 chr15: 67337017-67551787 chr15: 67245914-67753643 Deletion Peak 35 10q23.31 chr10: 89502327-90051809 chr10: 89574482-89607380 chr10: 83248858-135534747 Deletion Peak 23 6p25.3 chr6: 1613114-2256643 chr6: 1621843-2256643 chr6: 1626114-2752758 Deletion Peak 36 10q25.2 chr10: 114197471-115353755 chr10: 114708532-114929210 chr10: 83248858-135534747 Deletion Peak 38 11q22.3 chr11: 102958343-135006516 chr11: 108251085-108350263 chr11: 108179920-108470348 Deletion Peak 52 18q12.2 chr18: 35136370-39061915 chr18: 36781295-37333625 chr18: 35827844-46846953 Amplification Peak 8q21.13 chr8: 80636493-82552412 chr8: 81853752-81935079 chr8: 54646329-146364022 14 Amplification Peak 20q13.32 chr20: 56110288-57258354 chr20: 57000076-57085518 chr20: 24375411-63025520 43 Amplification Peak 17q11.2 chr17: 27339261-27528113 chr17: 27339592-27419750 chr17: 20042949-40168023 28 Deletion Peak 24 6p22.2 chr6: 25926929-26025173 chr6: 25932794-26025173 chr6: 25933563-26346501 Deletion Peak 15 4q22.1 chr4: 91143530-93226628 chr4: 91046982-92557520 chr4: 91103554-92561908 Deletion Peak 22 5q22.2 chr5: 111312546-112362638 chr5: 111747052-111761475 chr5: 50968806-135478060 Deletion Peak 59 22q13.32 chr22: 48649199-49178363 chr22: 48906309-49158314 chr22: 47983027-51304566 Deletion Peak 18 4q32.1 chr4: 156135292-162306004 chr4: 159683040-159830757 chr4: 152233433-191154276 Deletion Peak 17 4q31.3 chr4: 152679194-153694102 chr4: 153232273-153473069 chr4: 152233433-191154276 Deletion Peak 58 21q21.1 chr21: 23106546-26219369 chr21: 23248652-23494410 chr21: 1-31258004 Deletion Peak 53 18q21.2 chr18: 48472034-48707815 chr18: 48547928-48660122 chr18: 47049746-78077248 Amplification Peak 20q13.2 chr20: 52240629-52852159 chr20: 52246659-52447690 chr20: 24375411-63025520 42 Deletion Peak 57 21q11.2 chr21: 15555708-16334057 chr21: 15854887-15919066 chr21: 1-31258004

TABLE 11 Tier 2 selection of genomic markers used in recursive partitioning from the 102 focal regions. Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits Amplification Peak 11p15.5 chr11: 2091739-2302637 chr11: 2095340-2301396 chr11: 2095340-2305324 18 Amplification Peak 15q26.1 chr15: 84648780-102531392 chr15: 90811423-90958538 chr15: 90086447-91895585 25 Amplification Peak 16p11.2 chr16: 30548665-30684980 chr16: 30549334-30682578 chr16: 28556705-46663588 26 Deletion Peak 48 16q23.1 chr16: 78131135-79628242 chr16: 78131135-79286336 chr16: 78424695-79295468 Deletion Peak 10 3p26.3 chr3: 1-8350135 chr3: 1-2251569 chr3: 1-9456413 Deletion Peak 30 8p12 chr8: 33445578-37452445 chr8: 34944675-36494184 chr8: 35186331-35207233 Amplification Peak 17q24.2 chr17: 65638523-65873408 chr17: 65649475-65769071 chr17: 63042470-68655121 31 Amplification Peak 13q22.1 chr13: 73775176-74007122 chr13: 73906681-74004816 chr13: 1-115169878 23 Amplification Peak 7 5p12 chr5: 33430780-50470114 chr5: 43822799-43929095 chr5: 37334807-44266311 Deletion Peak 50 17q24.3 chr17: 68174484-70599305 chr17: 70337175-70590424 chr17: 70549664-70552757 Deletion Peak 45 15q21.1 chr15: 44850582-45321541 chr15: 44851811-45052539 chr15: 1-58781038 Amplification Peak 13q34 chr13: 110097815-111753132 chr13: 110614601-110852082 chr13: 1-115169878 24 Deletion Peak 29 8p21.3 chr8: 13423967-26607015 chr8: 21547484-21647267 chr8: 11646511-25738962 Amplification Peak 8 6p21.1 chr6: 43545080-44164949 chr6: 43765716-44163738 chr6: 36748055-52028937 Deletion Peak 3 1p33 chr1: 49187432-50544677 chr1: 48847112-50490440 chr1: 49196205-51396500 Deletion Peak 56 20p12.1 chr20: 13955189-16350354 chr20: 14416445-15462745 chr20: 14096517-16064189 Amplification Peak 7p11.2 chr7: 54949302-55950640 chr7: 55248172-55271747 chr7: 54949902-55955413 10 Deletion Peak 51 18p11.31 chr18: 3277394-4265401 chr18: 3441391-3481373 chr18: 3398771-3729936 Deletion Peak 33 10p15.3 chr10: 1-855610 chr10: 1-418075 chr10: 1-2055670 Amplification Peak 3 1q43 chr1: 201615295-249250621 chr1: 242413158-242638099 chr1: 242270003-249250621 Deletion Peak 21 5q12.1 chr5: 58263825-59784640 chr5: 58263825-59784640 chr5: 50968806-135478060 Amplification Peak 17q12 chr17: 37747533-38052599 chr17: 37950674-38031986 chr17: 20042949-40168023 29 Amplification Peak 4 2q33.1 chr2: 181446594-243199373 chr2: 199603526-199649638 chr2: 199525178-199824262 Amplification Peak 9 6q23.3 chr6: 135342981-135632150 chr6: 135513416-135593890 chr6: 133418393-138096856 Deletion Peak 39 12p13.2 chr12: 12412186-13039757 chr12: 12525464-12721981 chr12: 11739866-13828006 Deletion Peak 55 19p13.3 chr19: 1488247-1660256 chr19: 1488455-1660256 chr19: 1-5957502 Amplification Peak 8p11.23 chr8: 38162916-38237532 chr8: 38165117-38236937 chr8: 34342520-48854434 11 Amplification Peak 8q24.21 chr8: 128574277-128592142 chr8: 128574768-128591041 chr8: 54646329-146364022 16 Deletion Peak 13 3q26.31 chr3: 173995229-175766885 chr3: 174575326-175766885 chr3: 174646449-174998725 Deletion Peak 4 1p31.1 chr1: 68959091-82269682 chr1: 79308665-79566142 chr1: 54944113-149961894 Deletion Peak 49 17p12 chr17: 11466949-12461211 chr17: 11872374-11906034 chr17: 10231123-12752622 Deletion Peak 44 15q11.2 chr15: 25436434-25466900 chr15: 25438412-25459423 chr15: 1-58781038 Deletion Peak 37 10q26.3 chr10: 133107199-135534747 chr10: 135221096-135534747 chr10: 83248858-135534747 Amplification Peak 13q12.2 chr13: 28164386-28564331 chr13: 28174614-28222659 chr13: 1-115169878 22 Deletion Peak 19 4q35.1 chr4: 184432080-185262191 chr4: 184545375-185154488 chr4: 152233433-191154276 Deletion Peak 14 4p16.2 chr4: 1-9787265 chr4: 5915497-5925651 chr4: 1-11455571 Amplification Peak 8q12.2 chr8: 60847395-62906825 chr8: 61658252-61874896 chr8: 54646329-146364022 13 Deletion Peak 42 14q24.1 chr14: 68280014-69351476 chr14: 68284712-68948164 chr14: 68343659-68985929 Deletion Peak 5 1p21.1 chr1: 102460262-107618224 chr1: 104041213-104355050 chr1: 54944113-149961894 Deletion Peak 16 4q25 chr4: 109046573-109544048 chr4: 109451604-109544048 chr4: 109489936-109535239 Amplification Peak 20q11.21 chr20: 29981165-30284236 chr20: 30158807-30231055 chr20: 24375411-63025520 40 Deletion Peak 54 18q21.33 chr18: 60645473-61013467 chr18: 60788090-61013467 chr18: 47049746-78077248

TABLE 12 Tier 3 selection of genomic markers used in recursive partitioning from the 102 focal regions. Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits Amplification Peak 1 1p34.2 chr1: 39144054-44367347 chr1: 42834925-43114106 chr1: 42692914-43456374 Amplification Peak 5 3q29 chr3: 174745992-198022430 chr3: 195922177-195991311 chr3: 174746836-198022430 Amplification Peak 6 5p15.33 chr5: 1-6418038 chr5: 1-949725 chr5: 1-2807521 Amplification Peak 10q22.3 chr10: 79956009-83248579 chr10: 80445049-80732930 chr10: 77952482-83583616 17 Amplification Peak 11q13.3 chr11: 68746750-69827851 chr11: 69311828-69824706 chr11: 68748468-70760456 19 Amplification Peak 12p13.32 chr12: 3941807-4552801 chr12: 4257035-4414967 chr12: 1-8970181 20 Amplification Peak 12p11.22 chr12: 24880798-28477058 chr12: 27800441-27813180 chr12: 25955987-28156868 21 Amplification Peak 16q12.1 chr16: 52243935-52652774 chr16: 52383686-52652198 chr16: 51078632-53117566 27 Amplification Peak 17q23.2 chr17: 58400463-58674819 chr17: 58400997-58532661 chr17: 57045336-62714320 30 Amplification Peak 17q25.3 chr17: 77601682-77857881 chr17: 77766436-77856811 chr17: 75845339-81195210 32 Amplification Peak 18q11.2 chr18: 19517253-20155059 chr18: 19525020-20154578 chr18: 19243919-21268418 33 Amplification Peak 18q21.1 chr18: 46041609-46930382 chr18: 46474762-46604295 chr18: 46043163-46624631 34 Amplification Peak 19q13.11 chr19: 32439834-33021877 chr19: 32966965-32988344 chr19: 19939350-41312227 35 Amplification Peak 19q13.2 chr19: 39844313-40357920 chr19: 39848086-40009185 chr19: 19939350-41312227 36 Deletion Peak 1 1p36.31 chr1: 4843384-6053964 chr1: 5646446-6050774 chr1: 1-37080378 Deletion Peak 2 1p36.11 chr1: 26898389-27219375 chr1: 27139248-27185402 chr1: 1-37080378 Deletion Peak 6 2p25.3 chr2: 1-4752017 chr2: 1-488785 chr2: 1-5260278 Deletion Peak 7 2p21 chr2: 42587649-44009118 chr2: 43440855-43455807 chr2: 43159857-43470966 Deletion Peak 8 2q23.1 chr2: 147341956-149499455 chr2: 148437688-148750846 chr2: 148444810-148756213 Deletion Peak 9 2q37.3 chr2: 240321205-243199373 chr2: 240940975-241060875 chr2: 240589192-241997730 Deletion Peak 11 3p14.2 chr3: 58946448-61555632 chr3: 59692189-61457375 chr3: 59692189-61460946 Deletion Peak 20 5p15.33 chr5: 1-2750686 chr5: 1368344-2252637 chr5: 1-3864653 Deletion Peak 27 7q31.1 chr7: 109590674-111367757 chr7: 110232248-111358792 chr7: 110595801-110618403 Deletion Peak 31 8q11.1 chr8: 42874387-48101823 chr8: 42931769-48061147 chr8: 42932439-48062091 Deletion Peak 32 9p21.3 chr9: 21558582-22452906 chr9: 21995318-22021004 chr9: 21711940-22331169 Deletion Peak 41 12q24.33 chr12: 125048064-133851895 chr12: 131256822-131362341 chr12: 125246979-133851895 Deletion Peak 47 16p13.3 chr16: 5141600-8053542 chr16: 6056420-8053542 chr16: 5279421-7736962

TABLE 13 Contribution of each of the 180 regions to the random forest classification model. Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits Contribution value Deletion Peak 17 4q31.3 chr4: 152679194-153694102 chr4: 153232273-153473069 chr4: 152233433-191154276 5.69900368 Deletion Peak 19 4q35.1 chr4: 184432080-185262191 chr4: 184545375-185154488 chr4: 152233433-191154276 5.4602327 Deletion Peak 15 4q22.1 chr4: 91143530-93226628 chr4: 91046982-92557520 chr4: 91103554-92561908 5.40079966 Deletion Peak 18 4q32.1 chr4: 156135292-162306004 chr4: 159683040-159830757 chr4: 152233433-191154276 5.22218115 Whole arm deletion 29 4q NA NA chr4: 52660117-191154276 5.14074254 Deletion Peak 16 4q25 chr4: 109046573-109544048 chr4: 109451604-109544048 chr4: 109489936-109535239 5.12389105 Whole arm 4p NA NA chr4: 1-49660117 4.6643299 deletion 28 Amplification Peak 41 20q13.12 chr20: 42534268-43281676 chr20: 42537604-42773258 chr20: 24375411-63025520 3.29423738 Deletion Peak 4 1p31.1 chr1: 68959091-82269682 chr1: 79308665-79566142 chr1: 54944113-149961894 2.92406308 Deletion Peak 14 4p16.2 chr4: 1-9787265 chr4: 5915497-5925651 chr4: 1-11455571 2.77180108 Whole arm 22q NA NA chr22: 16000000-51304566 2.72591739 deletion 23 Deletion Peak 57 21q11.2 chr21: 15555708-16334057 chr21: 15854887-15919066 chr21: 1-31258004 2.55008085 Amplification 20q13.2 chr20: 52240629-52852159 chr20: 52246659-52447690 chr20: 24375411-63025520 2.53769321 Peak 42 Amplification 20q11.21 chr20: 29981165-30284236 chr20: 30158807-30231055 chr20: 24375411-63025520 2.46858084 Peak 40 Whole arm 20q NA NA chr20: 29369569-63025520 2.4607282 amplification 21 Deletion Peak 58 21q21.1 chr21: 23106546-26219369 chr21: 23248652-23494410 chr21: 1-31258004 2.46055021 Whole arm 21q NA NA chr21: 14288129-48129895 2.36208909 deletion 22 Amplification 20q13.32 chr20: 56110288-57258354 chr20: 57000076-57085518 chr20: 24375411-63025520 2.35785114 Peak 43 Deletion Peak 59 22q13.32 chr22: 48649199-49178363 chr22: 48906309-49158314 chr22: 47983027-51304566 2.27724108 Deletion Peak 34 10q21.1 chr10: 51561927-53481136 chr10: 51561927-54065263 chr10: 50763189-54253314 1.85840926 Deletion Peak 5 1p21.1 chr1: 102460262-107618224 chr1: 104041213-104355050 chr1: 54944113-149961894 1.85495579 Deletion Peak 38 11q22.3 chr11: 102958343-135006516 chr11: 108251085-108350263 chr11: 108179920-108470348 1.79129861 Deletion Peak 3 1p33 chr1: 49187432-50544677 chr1: 48847112-50490440 chr1: 49196205-51396500 1.75409699 Deletion Peak 37 10q26.3 chr10: 133107199-135534747 chr10: 135221096-135534747 chr10: 83248858-135534747 1.74689724 Whole arm 15q NA NA chr15: 20000000-102531392 1.74607014 deletion 9 Whole arm 10q NA NA chr10: 42254935-135534747 1.74534855 deletion 2 Deletion Peak 45 15q21.1 chr15: 44850582-45321541 chr15: 44851811-45052539 chr15: 1-58781038 1.74523402 Deletion Peak 52 18q12.2 chr18: 35136370-39061915 chr18: 36781295-37333625 chr18: 35827844-46846953 1.74103677 Deletion Peak 49 17p12 chr17: 11466949-12461211 chr17: 11872374-11906034 chr17: 10231123-12752622 1.74080473 Deletion Peak 35 10q23.31 chr10: 89502327-90051809 chr10: 89574482-89607380 chr10: 83248858-135534747 1.73841158 Whole arm 18p NA NA chr18: 1-15460898 1.69686457 deletion 14 Whole arm 18q NA NA chr18: 18460898-78077248 1.63024275 deletion 15 Deletion Peak 46 15q22.33 chr15: 67053712-67697647 chr15: 67337017-67551787 chr15: 67245914-67753643 1.61216031 Deletion Peak 53 18q21.2 chr18: 48472034-48707815 chr18: 48547928-48660122 chr18: 47049746-78077248 1.54801279 Amplification 20p12.3 chr20: 5376354-5742957 chr20: 5379141-5737687 chr20: 5156552-5961498 1.54217323 Peak 37 Deletion Peak 36 10q25.2 chr10: 114197471-115353755 chr10: 114708532-114929210 chr10: 83248858-135534747 1.49414539 Deletion Peak 54 18q21.33 chr18: 60645473-61013467 chr18: 60788090-61013467 chr18: 47049746-78077248 1.46051102 Deletion Peak 51 18p11.31 chr18: 3277394-4265401 chr18: 3441391-3481373 chr18: 3398771-3729936 1.44244308 Amplification 20p12.1 chr20: 16140291-16967195 chr20: 16488303-16962609 chr20: 16146669-16970141 1.39784163 Peak 38 Deletion Peak 28 8p23.3 chr8: 1-1449850 chr8: 1-623109 chr8: 1-10801317 1.376404 Whole arm 11p NA NA chr11: 1-51644205 1.36242884 deletion 3 Deletion Peak 2 1p36.11 chr1: 26898389-27219375 chr1: 27139248-27185402 chr1: 1-37080378 1.35158286 Deletion Peak 22 5q22.2 chr5: 111312546-112362638 chr5: 111747052-111761475 chr5: 50968806-135478060 1.32777145 Whole arm 17q NA NA chr17: 25263006-81195210 1.31992276 deletion 13 Deletion Peak 21 5q12.1 chr5: 58263825-59784640 chr5: 58263825-59784640 chr5: 50968806-135478060 1.31750542 Amplification 20p11.22 chr20: 22058560-22353663 chr20: 22063756-22350551 chr20: 20938975-24286806 1.29653026 Peak 39 Amplification 13q12.2 chr13: 28164386-28564331 chr13: 28174614-28222659 chr13: 1-115169878 1.29142193 Peak 22 Deletion Peak 44 15q11.2 chr15: 25436434-25466900 chr15: 25438412-25459423 chr15: 1-58781038 1.27544343 Deletion Peak 43 14q32.11 chr14: 78347564-107349540 chr14: 90999841-91286309 chr14: 90170502-92315681 1.2470974 Whole arm 11q NA NA chr11: 54644205-135006516 1.22838424 deletion 4 Whole arm 5q NA NA chr5: 49405641-180915260 1.21343422 deletion 31 Deletion Peak 42 14q24.1 chr14: 68280014-69351476 chr14: 68284712-68948164 chr14: 68343659-68985929 1.18921641 Amplification 13q22.1 chr13: 73775176-74007122 chr13: 73906681-74004816 chr13: 1-115169878 1.18041391 Peak 23 Amplification 8q22.3 chr8: 101853171-101878037 chr8: 101853464-101876083 chr8: 54646329-146364022 1.1639936 Peak 15 Whole arm 20p NA NA chr20: 1-26369569 1.11182166 amplification 20 Whole arm 17p NA NA chr17: 1-22263006 1.09115055 deletion 12 Whole arm 13q NA NA chr13: 19000000-115169878 1.08715413 amplification 7 Deletion Peak 40 12q21.2 chr12: 75602135-79819184 chr12: 76423769-76523220 chr12: 75648890-78593389 1.08195556 Deletion Peak 33 10p15.3 chr10: 1-855610 chr10: 1-418075 chr10: 1-2055670 1.03741963 Whole arm 10p NA NA chr10: 1-39254935 1.03431515 deletion 1 Whole arm 8p NA NA chr8: 1-43838887 1.01165483 deletion 36 Amplification 8p11.21 chr8: 41760295-42054539 chr8: 41767516-41796226 chr8: 34342520-48854434 1.00972856 Peak 12 Amplification 8q21.13 chr8: 80636493-82552412 chr8: 81853752-81935079 chr8: 54646329-146364022 1.00902364 Peak 14 Whole arm 8q NA NA chr8: 46838887-146364022 0.97550139 amplification 37 Amplification 13q34 chr13: 110097815-111753132 chr13: 110614601-110852082 chr13: 1-115169878 0.97236703 Peak 24 Whole arm 1p NA NA chr1: 1-121535434 0.9682743 deletion 18 Deletion Peak 29 8p21.3 chr8: 13423967-26607015 chr8: 21547484-21647267 chr8: 11646511-25738962 0.94172849 Amplification 8q24.21 chr8: 128574277-128592142 chr8: 128574768-128591041 chr8: 54646329-146364022 0.90669936 Peak 16 Deletion Peak 10 3p26.3 chr3: 1-8350135 chr3: 1-2251569 chr3: 1-9456413 0.90057889 Deletion Peak 56 20p12.1 chr20: 13955189-16350354 chr20: 14416445-15462745 chr20: 14096517-16064189 0.89553463 Amplification 17q12 chr17: 37747533-38052599 chr17: 37950674-38031986 chr17: 20042949-40168023 0.8947382 Peak 29 Deletion Peak 30 8p12 chr8: 33445578-37452445 chr8: 34944675-36494184 chr8: 35186331-35207233 0.89027155 Whole arm 14q NA NA chr14: 19000000-107349540 0.87610091 deletion 8 Deletion Peak 55 19p13.3 chr19: 1488247-1660256 chr19: 1488455-1660256 chr19: 1-5957502 0.86068674 Deletion Peak 1 1p36.31 chr1: 4843384-6053964 chr1: 5646446-6050774 chr1: 1-37080378 0.85950877 Whole arm 9p NA NA chr9: 1-47367679 0.84910578 deletion 38 Deletion Peak 50 17q24.3 chr17: 68174484-70599305 chr17: 70337175-70590424 chr17: 70549664-70552757 0.82566352 Amplification 17q11.2 chr17: 27339261-27528113 chr17: 27339592-27419750 chr17: 20042949-40168023 0.80753708 Peak 28 Amplification 8p11.23 chr8: 38162916-38237532 chr8: 38165117-38236937 chr8: 34342520-48854434 0.79953951 Peak 11 Amplification 1q43 chr1: 201615295-249250621 chr1: 242413158-242638099 chr1: 242270003-249250621 0.78150602 Peak 3 Whole arm 7q NA NA chr7: 61054331-159138663 0.77800193 amplification 35 Amplification 8q12.2 chr8: 60847395-62906825 chr8: 61658252-61874896 chr8: 54646329-146364022 0.77096113 Peak 13 Whole arm 7p NA NA chr7: 1-58054331 0.76807364 amplification 34 Amplification 5p12 chr5: 33430780-50470114 chr5: 43822799-43929095 chr5: 37334807-44266311 0.75708381 Peak 7 Deletion Peak 12 3p13 chr3: 70014100-71250049 chr3: 70976616-71182883 chr3: 70977475-71315576 0.75572694 Deletion Peak 32 9p21.3 chr9: 21558582-22452906 chr9: 21995318-22021004 chr9: 21711940-22331169 0.75281938 Amplification 5p15.33 chr5: 1-6418038 chr5: 1-949725 chr5: 1-2807521 0.75064607 Peak 6 Amplification 16q12.1 chr16: 52243935-52652774 chr16: 52383686-52652198 chr16: 51078632-53117566 0.72390332 Peak 27 Whole arm 16p NA NA chr16: 1-35335801 0.71183633 amplification 10 Amplification 7p11.2 chr7: 54949302-55950640 chr7: 55248172-55271747 chr7: 54949902-55955413 0.71128453 Peak 10 Deletion Peak 11 3p14.2 chr3: 58946448-61555632 chr3: 59692189-61457375 chr3: 59692189-61460946 0.69805324 Whole arm 16q NA NA chr16: 38335801-90354753 0.6977664 amplification 11 Amplification 16p11.2 chr16: 30548665-30684980 chr16: 30549334-30682578 chr16: 28556705-46663588 0.68677078 Peak 26 Whole arm 17q NA NA chr17: 25263006-81195210 0.68298273 amplification 13 Deletion Peak 26 6q26 chr6: 161540781-163179430 chr6: 161540781-163179430 chr6: 160448048-171115067 0.68131369 Amplification 6p21.1 chr6: 43545080-44164949 chr6: 43765716-44163738 chr6: 36748055-52028937 0.68018519 Peak 8 Whole arm 12q NA NA chr12: 37856694-133851895 0.67955302 deletion 6 Deletion Peak 25 6q21 chr6: 91006553-129206367 chr6: 111544567-112706964 chr6: 108785353-116683959 0.67397177 Amplification Peak 2 1q22 chr1: 120494739-199253746 chr1: 155143717-155177826 chr1: 120497533-175439985 0.6692668 Whole arm 6p NA NA chr6: 1-58830166 0.66083392 amplification 32 Whole arm 8p NA NA chr8: 1-43838887 0.65986144 amplification 36 Amplification 12p13.32 chr12: 3941807-4552801 chr12: 4257035-4414967 chr12: 1-8970181 0.65326501 Peak 20 Whole arm 1q NA NA chr1: 124535434-249250621 0.63810089 amplification 19 Whole arm 5p NA NA chr5: 1-46405641 0.62977686 deletion 30 Deletion Peak 39 12p13.2 chr12: 12412186-13039757 chr12: 12525464-12721981 chr12: 11739866-13828006 0.61944112 Whole arm 19p NA NA chr19: 1-24681782 0.61447685 deletion 16 Amplification 19q13.2 chr19: 39844313-40357920 chr19: 39848086-40009185 chr19: 19939350-41312227 0.61443667 Peak 36 Amplification 12p11.22 chr12: 24880798-28477058 chr12: 27800441-27813180 chr12: 25955987-28156868 0.60473038 Peak 21 Amplification 6q23.3 chr6: 135342981-135632150 chr6: 135513416-135593890 chr6: 133418393-138096856 0.6007847 Peak 9 Whole arm 1q NA NA chr1: 124535434-249250621 0.5932403 deletion 19 Deletion Peak 31 8q11.1 chr8: 42874387-48101823 chr8: 42931769-48061147 chr8: 42932439-48062091 0.59224336 Whole arm 19q NA NA chr19: 27681782-59128983 0.58885616 deletion 17 Whole arm 12p NA NA chr12: 1-34856694 0.58033903 deletion 5 Whole arm 5p NA NA chr5: 1-46405641 0.58007436 amplification 30 Deletion Peak 23 6p25.3 chr6: 1613114-2256643 chr6: 1621843-2256643 chr6: 1626114-2752758 0.57614983 Amplification 17q25.3 chr17: 77601682-77857881 chr17: 77766436-77856811 chr17: 75845339-81195210 0.57546275 Peak 32 Amplification 2q33.1 chr2: 181446594-243199373 chr2: 199603526-199649638 chr2: 199525178-199824262 0.57035447 Peak 4 Whole arm 12p NA NA chr12: 1-34856694 0.56509266 amplification 5 Whole arm 6q NA NA chr6: 61830166-171115067 0.55451621 deletion 33 Whole arm 9q NA NA chr9: 50367679-141213431 0.54581935 deletion 39 Amplification 3q29 chr3: 174745992-198022430 chr3: 195922177-195991311 chr3: 174746836-198022430 0.54264532 Peak 5 Amplification 11p15.5 chr11: 2091739-2302637 chr11: 2095340-2301396 chr11: 2095340-2305324 0.54017534 Peak 18 Amplification 17q24.2 chr17: 65638523-65873408 chr17: 65649475-65769071 chr17: 63042470-68655121 0.53976335 Peak 31 Deletion Peak 41 12q24.33 chr12: 125048064-133851895 chr12: 131256822-131362341 chr12: 125246979-133851895 0.53826885 Whole arm 2q NA NA chr2: 95326171-243199373 0.53771069 amplification 25 Whole arm 6q NA NA chr6: 61830166-171115067 0.53538285 amplification 33 Deletion Peak 20 5p15.33 chr5: 1-2750686 chr5: 1368344-2252637 chr5: 1-3864653 0.52968199 Whole arm 3p NA NA chr3: 1-90504854 0.52919712 deletion 26 Amplification 17q23.2 chr17: 58400463-58674819 chr17: 58400997-58532661 chr17: 57045336-62714320 0.52759456 Peak 30 Whole arm 9p NA NA chr9: 1-47367679 0.52569831 amplification 38 Deletion Peak 6 2p25.3 chr2: 1-4752017 chr2: 1-488785 chr2: 1-5260278 0.52195842 Whole arm 6p NA NA chr6: 1-58830166 0.51638946 deletion 32 Amplification 19q13.11 chr19: 32439834-33021877 chr19: 32966965-32988344 chr19: 19939350-41312227 0.51402152 Peak 35 Deletion Peak 24 6p22.2 chr6: 25926929-26025173 chr6: 25932794-26025173 chr6: 25933563-26346501 0.51056665 Whole arm 2p NA NA chr2: 1-92326171 0.50462529 amplification 24 Whole arm 3q NA NA chr3: 93504854-198022430 0.48576757 amplification 27 Whole arm 19q NA NA chr19: 27681782-59128983 0.48190073 amplification 17 Deletion Peak 13 3q26.31 chr3: 173995229-175766885 chr3: 174575326-175766885 chr3: 174646449-174998725 0.47316393 Whole arm 12q NA NA chr12: 37856694-133851895 0.4694395 amplification 6 Whole arm 20p NA NA chr20: 1-26369569 0.46181551 deletion 20 Amplification 11q13.3 chr11: 68746750-69827851 chr11: 69311828-69824706 chr11: 68748468-70760456 0.45349829 Peak 19 Deletion Peak 48 16q23.1 chr16: 78131135-79628242 chr16: 78131135-79286336 chr16: 78424695-79295468 0.45142138 Deletion Peak 47 16p13.3 chr16: 5141600-8053542 chr16: 6056420-8053542 chr16: 5279421-7736962 0.45028421 Whole arm 9q NA NA chr9: 50367679-141213431 0.43896029 amplification 39 Whole arm 10p NA NA chr10: 1-39254935 0.43821908 amplification 1 Amplification 15q26.1 chr15: 84648780-102531392 chr15: 90811423-90958538 chr15: 90086447-91895585 0.43390108 Peak 25 Whole arm 19p NA NA chr19: 1-24681782 0.42292166 amplification 16 Whole arm 11p NA NA chr11: 1-51644205 0.42185291 amplification 3 Whole arm 21q NA NA chr21: 14288129-48129895 0.38128102 amplification 22 Whole arm 17p NA NA chr17: 1-22263006 0.3799839 amplification 12 Whole arm 3q NA NA chr3: 93504854-198022430 0.37733862 deletion 27 Whole arm 3p NA NA chr3: 1-90504854 0.3694481 amplification 26 Whole arm 11q NA NA chr11: 54644205-135006516 0.36247292 amplification 4 Whole arm 16p NA NA chr16: 1-35335801 0.36136172 deletion 10 Deletion Peak 9 2q37.3 chr2: 240321205-243199373 chr2: 240940975-241060875 chr2: 240589192-241997730 0.34823854 Whole arm 1p NA NA chr1: 1-121535434 0.34348283 amplification 18 Whole arm 16q NA NA chr16: 38335801-90354753 0.32026275 deletion 11 Deletion Peak 7 2p21 chr2: 42587649-44009118 chr2: 43440855-43455807 chr2: 43159857-43470966 0.31250652 Deletion Peak 8 2q23.1 chr2: 147341956-149499455 chr2: 148437688-148750846 chr2: 148444810-148756213 0.29511207 Whole arm 5q NA NA chr5: 49405641-180915260 0.2792709 amplification 31 Amplification 10q22.3 chr10: 79956009-83248579 chr10: 80445049-80732930 chr10: 77952482-83583616 0.27562286 Peak 17 Amplification 18q11.2 chr18: 19517253-20155059 chr18: 19525020-20154578 chr18: 19243919-21268418 0.2636361 Peak 33 Whole arm 14q NA NA chr14: 19000000-107349540 0.25989981 amplification 8 Amplification 1p34.2 chr1: 39144054-44367347 chr1: 42834925-43114106 chr1: 42692914-43456374 0.25159063 Peak 1 Whole arm 8q NA NA chr8: 46838887-146364022 0.24836297 deletion 37 Whole arm 10q NA NA chr10: 42254935-135534747 0.21366949 amplification 2 Whole arm 18p NA NA chr18: 1-15460898 0.20445617 amplification 14 Whole arm 4p NA NA chr4: 1-49660117 0.18414829 amplification 28 Deletion Peak 27 7q31.1 chr7: 109590674-111367757 chr7: 110232248-111358792 chr7: 110595801-110618403 0.15773653 Whole arm 18q NA NA chr18: 18460898-78077248 0.14698558 amplification 15 Amplification 18q21.1 chr18: 46041609-46930382 chr18: 46474762-46604295 chr18: 46043163-46624631 0.145565 Peak 34 Whole arm 7q NA NA chr7: 61054331-159138663 0.13516126 deletion 35 Whole arm 13q NA NA chr13: 19000000-115169878 0.13461326 deletion 7 Whole arm 2p NA NA chr2: 1-92326171 0.11809222 deletion 24 Whole arm 2q NA NA chr2: 95326171-243199373 0.11400227 deletion 25 Whole arm 15q NA NA chr15: 20000000-102531392 0.10837076 amplification 9 Whole arm 22q NA NA chr22: 16000000-51304566 0.09878651 amplification 23 Whole arm 4q NA NA chr4: 52660117-191154276 0.09805239 amplification 29 Whole arm 7p NA NA chr7: 1-58054331 0.04804664 deletion 34 Whole arm 20q NA NA chr20: 29369569-63025520 0 deletion 21

TABLE 14 Contribution of each of the 102 focal regions to the random forest classification model. Contribution Unique Name Descriptor Wide Peak Limits Peak Limits Region Limits value Deletion Peak 16 4q25 chr4: 109046573-109544048 chr4: 109451604-109544048 chr4: 109489936-109535239 9.194419 Deletion Peak 18 4q32.1 chr4: 156135292-162306004 chr4: 159683040-159830757 chr4: 152233433-191154276 8.1782609 Deletion Peak 17 4q31.3 chr4: 152679194-153694102 chr4: 153232273-153473069 chr4: 152233433-191154276 8.0446448 Deletion Peak 15 4q22.1 chr4: 91143530-93226628 chr4: 91046982-92557520 chr4: 91103554-92561908 7.8661453 Deletion Peak 19 4q35.1 chr4: 184432080-185262191 chr4: 184545375-185154488 chr4: 152233433-191154276 7.1401903 Amplification 20q13.12 chr20: 42534268-43281676 chr20: 42537604-42773258 chr20: 24375411-63025520 4.6635259 Peak 41 Amplification 20q11.21 chr20: 29981165-30284236 chr20: 30158807-30231055 chr20: 24375411-63025520 4.4202524 Peak 40 Deletion Peak 14 4p16.2 chr4: 1-9787265 chr4: 5915497-5925651 chr4: 1-11455571 4.4096883 Amplification 20q13.2 chr20: 52240629-52852159 chr20: 52246659-52447690 chr20: 24375411-63025520 4.2672955 Peak 42 Deletion Peak 59 22q13.32 chr22: 48649199-49178363 chr22: 48906309-49158314 chr22: 47983027-51304566 4.1267928 Deletion Peak 57 21q11.2 chr21: 15555708-16334057 chr21: 15854887-15919066 chr21: 1-31258004 4.0776699 Deletion Peak 58 21q21.1 chr21: 23106546-26219369 chr21: 23248652-23494410 chr21: 1-31258004 3.9182542 Amplification 20q13.32 chr20: 56110288-57258354 chr20: 57000076-57085518 chr20: 24375411-63025520 3.5799093 Peak 43 Deletion Peak 46 15q22.33 chr15: 67053712-67697647 chr15: 67337017-67551787 chr15: 67245914-67753643 3.455251 Deletion Peak 35 10q23.31 chr10: 89502327-90051809 chr10: 89574482-89607380 chr10: 83248858-135534747 3.369556 Deletion Peak 34 10q21.1 chr10: 51561927-53481136 chr10: 51561927-54065263 chr10: 50763189-54253314 3.1436983 Deletion Peak 53 18q21.2 chr18: 48472034-48707815 chr18: 48547928-48660122 chr18: 47049746-78077248 2.905616 Deletion Peak 36 10q25.2 chr10: 114197471-115353755 chr10: 114708532-114929210 chr10: 83248858-135534747 2.7938966 Deletion Peak 4 1p31.1 chr1: 68959091-82269682 chr1: 79308665-79566142 chr1: 54944113-149961894 2.7530879 Deletion Peak 5 1p21.1 chr1: 102460262-107618224 chr1: 104041213-104355050 chr1: 54944113-149961894 2.6974638 Deletion Peak 52 18q12.2 chr18: 35136370-39061915 chr18: 36781295-37333625 chr18: 35827844-46846953 2.6594014 Deletion Peak 54 18q21.33 chr18: 60645473-61013467 chr18: 60788090-61013467 chr18: 47049746-78077248 2.5200778 Amplification 20p12.1 chr20: 16140291-16967195 chr20: 16488303-16962609 chr20: 16146669-16970141 2.5116485 Peak 38 Deletion Peak 38 11q22.3 chr11: 102958343-135006516 chr11: 108251085-108350263 chr11: 108179920-108470348 2.4935124 Deletion Peak 3 1p33 chr1: 49187432-50544677 chr1: 48847112-50490440 chr1: 49196205-51396500 2.4544835 Deletion Peak 44 15q11.2 chr15: 25436434-25466900 chr15: 25438412-25459423 chr15: 1-58781038 2.3805641 Deletion Peak 37 10q26.3 chr10: 133107199-135534747 chr10: 135221096-135534747 chr10: 83248858-135534747 2.3715158 Deletion Peak 51 18p11.31 chr18: 3277394-4265401 chr18: 3441391-3481373 chr18: 3398771-3729936 2.3395225 Amplification 20p11.22 chr20: 22058560-22353663 chr20: 22063756-22350551 chr20: 20938975-24286806 2.3155324 Peak 39 Deletion Peak 49 17p12 chr17: 11466949-12461211 chr17: 11872374-11906034 chr17: 10231123-12752622 2.2734537 Deletion Peak 45 15q21.1 chr15: 44850582-45321541 chr15: 44851811-45052539 chr15: 1-58781038 2.2056725 Deletion Peak 22 5q22.2 chr5: 111312546-112362638 chr5: 111747052-111761475 chr5: 50968806-135478060 2.1163858 Amplification 20p12.3 chr20: 5376354-5742957 chr20: 5379141-5737687 chr20: 5156552-5961498 2.064109 Peak 37 Deletion Peak 28 8p23.3 chr8: 1-1449850 chr8: 1-623109 chr8: 1-10801317 2.0464708 Amplification 13q12.2 chr13: 28164386-28564331 chr13: 28174614-28222659 chr13: 1-115169878 2.0138841 Peak 22 Deletion Peak 21 5q12.1 chr5: 58263825-59784640 chr5: 58263825-59784640 chr5: 50968806-135478060 1.9727809 Amplification 13q22.1 chr13: 73775176-74007122 chr13: 73906681-74004816 chr13: 1-115169878 1.9642941 Peak 23 Amplification 8q21.13 chr8: 80636493-82552412 chr8: 81853752-81935079 chr8: 54646329-146364022 1.7754935 Peak 14 Deletion Peak 33 10p15.3 chr10: 1-855610 chr10: 1-418075 chr10: 1-2055670 1.7489137 Deletion Peak 42 14q24.1 chr14: 68280014-69351476 chr14: 68284712-68948164 chr14: 68343659-68985929 1.7375301 Deletion Peak 40 12q21.2 chr12: 75602135-79819184 chr12: 76423769-76523220 chr12: 75648890-78593389 1.7138062 Deletion Peak 43 14q32.11 chr14: 78347564-107349540 chr14: 90999841-91286309 chr14: 90170502-92315681 1.7100382 Amplification 8q22.3 chr8: 101853171-101878037 chr8: 101853464-101876083 chr8: 54646329-146364022 1.6977776 Peak 15 Deletion Peak 2 1p36.11 chr1: 26898389-27219375 chr1: 27139248-27185402 chr1: 1-37080378 1.655325 Deletion Peak 1 1p36.31 chr1: 4843384-6053964 chr1: 5646446-6050774 chr1: 1-37080378 1.6275767 Amplification 13q34 chr13: 110097815-111753132 chr13: 110614601-110852082 chr13: 1-115169878 1.6177405 Peak 24 Deletion Peak 56 20p12.1 chr20: 13955189-16350354 chr20: 14416445-15462745 chr20: 14096517-16064189 1.5555618 Amplification 8q12.2 chr8: 60847395-62906825 chr8: 61658252-61874896 chr8: 54646329-146364022 1.5323055 Peak 13 Deletion Peak 29 8p21.3 chr8: 13423967-26607015 chr8: 21547484-21647267 chr8: 11646511-25738962 1.5316374 Deletion Peak 55 19p13.3 chr19: 1488247-1660256 chr19: 1488455-1660256 chr19: 1-5957502 1.5195977 Deletion Peak 30 8p12 chr8: 33445578-37452445 chr8: 34944675-36494184 chr8: 35186331-35207233 1.5162631 Amplification 8p11.21 chr8: 41760295-42054539 chr8: 41767516-41796226 chr8: 34342520-48854434 1.5015065 Peak 12 Amplification 5p12 chr5: 33430780-50470114 chr5: 43822799-43929095 chr5: 37334807-44266311 1.4519356 Peak 7 Amplification 8q24.21 chr8: 128574277-128592142 chr8: 128574768-128591041 chr8: 54646329-146364022 1.4373339 Peak 16 Deletion Peak 12 3p13 chr3: 70014100-71250049 chr3: 70976616-71182883 chr3: 70977475-71315576 1.4356909 Deletion Peak 10 3p26.3 chr3: 1-8350135 chr3: 1-2251569 chr3: 1-9456413 1.4256335 Amplification 7p11.2 chr7: 54949302-55950640 chr7: 55248172-55271747 chr7: 54949902-55955413 1.3851619 Peak 10 Amplification 1q43 chr1: 201615295-249250621 chr1: 242413158-242638099 chr1: 242270003-249250621 1.3355112 Peak 3 Deletion Peak 26 6q26 chr6: 161540781-163179430 chr6: 161540781-163179430 chr6: 160448048-171115067 1.3326207 Deletion Peak 25 6q21 chr6: 91006553-129206367 chr6: 111544567-112706964 chr6: 108785353-116683959 1.3147804 Deletion Peak 50 17q24.3 chr17: 68174484-70599305 chr17: 70337175-70590424 chr17: 70549664-70552757 1.2848234 Amplification 6p21.1 chr6: 43545080-44164949 chr6: 43765716-44163738 chr6: 36748055-52028937 1.2774639 Peak 8 Amplification 5p15.33 chr5: 1-6418038 chr5: 1-949725 chr5: 1-2807521 1.2446252 Peak 6 Amplification 8p11.23 chr8: 38162916-38237532 chr8: 38165117-38236937 chr8: 34342520-48854434 1.2319335 Peak 11 Deletion Peak 32 9p21.3 chr9: 21558582-22452906 chr9: 21995318-22021004 chr9: 21711940-22331169 1.1988554 Amplification 16p11.2 chr16: 30548665-30684980 chr16: 30549334-30682578 chr16: 28556705-46663588 1.197811 Peak 26 Deletion Peak 11 3p14.2 chr3: 58946448-61555632 chr3: 59692189-61457375 chr3: 59692189-61460946 1.1379309 Amplification 1q22 chr1: 120494739-199253746 chr1: 155143717-155177826 chr1: 120497533-175439985 1.1037294 Peak 2 Deletion Peak 41 12q24.33 chr12: 125048064-133851895 chr12: 131256822-131362341 chr12: 125246979-133851895 1.092504 Amplification 17q11.2 chr17: 27339261-27528113 chr17: 27339592-27419750 chr17: 20042949-40168023 1.0736711 Peak 28 Amplification 17q12 chr17: 37747533-38052599 chr17: 37950674-38031986 chr17: 20042949-40168023 1.061722 Peak 29 Deletion Peak 20 5p15.33 chr5: 1-2750686 chr5: 1368344-2252637 chr5: 1-3864653 1.0603831 Amplification 16q12.1 chr16: 52243935-52652774 chr16: 52383686-52652198 chr16: 51078632-53117566 1.0570224 Peak 27 Amplification 12p11.22 chr12: 24880798-28477058 chr12: 27800441-27813180 chr12: 25955987-28156868 1.0564938 Peak 21 Amplification 2q33.1 chr2: 181446594-243199373 chr2: 199603526-199649638 chr2: 199525178-199824262 1.0392578 Peak 4 Amplification 17q25.3 chr17: 77601682-77857881 chr17: 77766436-77856811 chr17: 75845339-81195210 1.0214531 Peak 32 Deletion Peak 39 12p13.2 chr12: 12412186-13039757 chr12: 12525464-12721981 chr12: 11739866-13828006 1.01047 Amplification 3q29 chr3: 174745992-198022430 chr3: 195922177-195991311 chr3: 174746836-198022430 1.0074218 Peak 5 Amplification 6q23.3 chr6: 135342981-135632150 chr6: 135513416-135593890 chr6: 133418393-138096856 0.9983965 Peak 9 Deletion Peak 24 6p22.2 chr6: 25926929-26025173 chr6: 25932794-26025173 chr6: 25933563-26346501 0.9867404 Amplification 17q24.2 chr17: 65638523-65873408 chr17: 65649475-65769071 chr17: 63042470-68655121 0.9853368 Peak 31 Amplification 17q23.2 chr17: 58400463-58674819 chr17: 58400997-58532661 chr17: 57045336-62714320 0.928049 Peak 30 Deletion Peak 31 8q11.1 chr8: 42874387-48101823 chr8: 42931769-48061147 chr8: 42932439-48062091 0.9098856 Amplification 11p15.5 chr11: 2091739-2302637 chr11: 2095340-2301396 chr11: 2095340-2305324 0.9026687 Peak 18 Deletion Peak 23 6p25.3 chr6: 1613114-2256643 chr6: 1621843-2256643 chr6: 1626114-2752758 0.8969569 Amplification 12p13.32 chr12: 3941807-4552801 chr12: 4257035-4414967 chr12: 1-8970181 0.892304 Peak 20 Amplification 19q13.2 chr19: 39844313-40357920 chr19: 39848086-40009185 chr19: 19939350-41312227 0.8844445 Peak 36 Deletion Peak 48 16q23.1 chr16: 78131135-79628242 chr16: 78131135-79286336 chr16: 78424695-79295468 0.8843983 Amplification 19q13.11 chr19: 32439834-33021877 chr19: 32966965-32988344 chr19: 19939350-41312227 0.880044 Peak 35 Deletion Peak 6 2p25.3 chr2: 1-4752017 chr2: 1-488785 chr2: 1-5260278 0.7876138 Deletion Peak 13 3q26.31 chr3: 173995229-175766885 chr3: 174575326-175766885 chr3: 174646449-174998725 0.7648052 Deletion Peak 47 16p13.3 chr16: 5141600-8053542 chr16: 6056420-8053542 chr16: 5279421-7736962 0.6998853 Amplification 11q13.3 chr11: 68746750-69827851 chr11: 69311828-69824706 chr11: 68748468-70760456 0.6309478 Peak 19 Amplification 15q26.1 chr15: 84648780-102531392 chr15: 90811423-90958538 chr15: 90086447-91895585 0.5231053 Peak 25 Deletion Peak 9 2q37.3 chr2: 240321205-243199373 chr2: 240940975-241060875 chr2: 240589192-241997730 0.5216232 Deletion Peak 8 2q23.1 chr2: 147341956-149499455 chr2: 148437688-148750846 chr2: 148444810-148756213 0.5056672 Amplification 18q11.2 chr18: 19517253-20155059 chr18: 19525020-20154578 chr18: 19243919-21268418 0.4808792 Peak 33 Deletion Peak 7 2p21 chr2: 42587649-44009118 chr2: 43440855-43455807 chr2: 43159857-43470966 0.4489627 Amplification 1p34.2 chr1: 39144054-44367347 chr1: 42834925-43114106 chr1: 42692914-43456374 0.4346417 Peak 1 Amplification 10q22.3 chr10: 79956009-83248579 chr10: 80445049-80732930 chr10: 77952482-83583616 0.3836683 Peak 17 Amplification 18q21.1 chr18: 46041609-46930382 chr18: 46474762-46604295 chr18: 46043163-46624631 0.2879049 Peak 34 Deletion Peak 27 7q31.1 chr7: 109590674-111367757 chr7: 110232248-111358792 chr7: 110595801-110618403 0.2331979

TABLE 15 Comparison between recursive partitioning tiers and the contribution to the random forest model for each of the 180 genomic regions. Genomic regions are listed by their descriptor name. Full information of these markers (e.g. peak limits and region limits) can be retrieved from Table 1 using the descriptor name. Descriptor name Contribution Tier 1 Tier 2 Tier 3 Tier 4 del_4q31.3 5.69900368 del_4q31.3 — — — del_4q35.1 5.4602327 — del_4q35.1 — — del_4q22.1 5.40079966 del_4q22.1 — — — del_4q32.1 5.22218115 del_4q32.1 — — — wa_del_4q 5.14074254 — wa_del_4q — — del_4q25 5.12389105 — del_4q25 — — wa_del_4p 4.6643299 — wa_del_4p — — amp_20q13.12 3.29423738 amp_20q13.12 — — — del_1p31.1 2.92406308 — del_1p31.1 — — del_4p16.2 2.77180108 — — del_4p16.2 — wa_del_22q 2.72591739 wa_del_22q — — — del_21q11.2 2.55008085 del_21q11.2 — — — amp_20q13.2 2.53769321 amp_20q13.2 — — — amp_20q11.21 2.46858084 — amp_20q11.21 — — wa_amp_20q 2.4607282 — wa_amp_20q — — del_21q21.1 2.46055021 del_21q21.1 — — — wa_del_21q 2.36208909 wa_del_21q — — — amp_20q13.32 2.35785114 amp_20q13.32 — — — del_22q13.32 2.27724108 del_22q13.32 — — — del_10q21.1 1.85840926 del_10q21.1 — — — del_1p21.1 1.85495579 — del_1p21.1 — — del_11q22.3 1.79129861 del_11q22.3 — — — del_1p33 1.75409699 — del_1p33 — — del_10q26.3 1.74689724 — del_10q26.3 — — wa_del_15q 1.74607014 — wa_del_15q — — wa_del_10q 1.74534855 wa_del_10q — — — del_15q21.1 1.74523402 — — del_15q21.1 — del_18q12.2 1.74103677 del_18q12.2 — — — del_17p12 1.74080473 — del_17p12 — — del_10q23.31 1.73841158 del_10q23.31 — — — wa_del_18p 1.69686457 — wa_del_18p — — wa_del_18q 1.63024275 wa_del_18q — — — del_15q22.33 1.61216031 — del_15q22.33 — — del_18q21.2 1.54801279 del_18q21.2 — — — amp_20p12.3 1.54217323 amp_20p12.3 — — — del_10q25.2 1.49414539 del_10q25.2 — — — del_18q21.33 1.46051102 — del_18q21.33 — — del_18p11.31 1.44244308 — del_18p11.31 — — amp_20p12.1 1.39784163 amp_20p12.1 — — — del_8p23.3 1.376404 del_8p23.3 — — — wa_del_11p 1.36242884 — — wa_del_11p — del_1p36.11 1.35158286 — — del_1p36.11 — del_5q22.2 1.32777145 del_5q22.2 — — — wa_del_17q 1.31992276 — wa_del_17q — — del_5q12.1 1.31750542 — del_5q12.1 — — amp_20p11.22 1.29653026 — amp_20p11.22 — — amp_13q12.2 1.29142193 — amp_13q12.2 — — del_15q11.2 1.27544343 — — del_15q11.2 — del_14q32.11 1.2470974 — del_14q32.11 — — wa_del_11q 1.22838424 — wa_del_11q — — wa_del_5q 1.21343422 wa_del_5q — — — del_14q24.1 1.18921641 — del_14q24.1 — — amp_13q22.1 1.18041391 — — amp_13q22.1 — amp_8q22.3 1.1639936 — amp_8q22.3 — — wa_amp_20p 1.11182166 wa_amp_20p — — — wa_del_17p 1.09115055 — wa_del_17p — — wa_amp_13q 1.08715413 — — wa_amp_13q — del_12q21.2 1.08195556 del_12q21.2 — — — del_10p15.3 1.03741963 — — del_10p15.3 — wa_del_10p 1.03431515 — wa_del_10p — — wa_del_8p 1.01165483 — — wa_del_8p — amp_8p11.21 1.00972856 amp_8p11.21 — — — amp_8q21.13 1.00902364 — amp_8q21.13 — — wa_amp_8q 0.97550139 — wa_amp_8q — — amp_13q34 0.97236703 — — amp_13q34 — wa_del_1p 0.9682743 — — wa_del_1p — del_8p21.3 0.94172849 — — del_8p21.3 — amp_8q24.21 0.90669936 — amp_8q24.21 — — del_3p26.3 0.90057889 — del_3p26.3 — — del_20p12.1 0.89553463 del_20p12.1 — — — amp_17q12 0.8947382 amp_17q12 — — — del_8p12 0.89027155 — del_8p12 — — wa_del_14q 0.87610091 — wa_del_14q — — del_19p13.3 0.86068674 — del_19p13.3 — — del_1p36.31 0.85950877 — — del_1p36.31 — wa_del_9p 0.84910578 wa_del_9p — — — del_17q24.3 0.82566352 — del_17q24.3 — — amp_17q11.2 0.80753708 amp_17q11.2 — — — amp_8p11.23 0.79953951 — amp_8p11.23 — — amp_1q43 0.78150602 — amp_1q43 — — wa_amp_7q 0.77800193 — — — wa_amp_7q amp_8q12.2 0.77096113 — amp_8q12.2 — — wa_amp_7p 0.76807364 — wa_amp_7p — — amp_5p12 0.75708381 — — — amp_5p12 del_3p13 0.75572694 — del_3p13 — — del_9p21.3 0.75281938 — — del_9p21.3 — amp_5p15.33 0.75064607 — — — amp_5p15.33 amp_16q12.1 0.72390332 — — amp_16q12.1 — wa_amp_16p 0.71183633 — — — wa_amp_16p amp_7p11.2 0.71128453 — — — amp_7p11.2 del_3p14.2 0.69805324 del_3p14.2 — — — wa_amp_16q 0.6977664 — — wa_amp_16q — amp_16p11.2 0.68677078 — — amp_16p11.2 — wa_amp_17q 0.68298273 — — wa_amp_17q — del_6q26 0.68131369 del_6q26 — — — amp_6p21.1 0.68018519 — amp_6p21.1 — — wa_del_12q 0.67955302 — — wa_del_12q — del_6q21 0.67397177 del_6q21 — — — amp_1q22 0.6692668 — — amp_1q22 — wa_amp_6p 0.66083392 — — wa_amp_6p — wa_amp_8p 0.65986144 — — wa_amp_8p — amp_12p13.32 0.65326501 — — — amp_12p13.32 wa_amp_1q 0.63810089 — — wa_amp_1q — wa_del_5p 0.62977686 — — wa_del_5p — del_12p13.2 0.61944112 — del_12p13.2 — — wa_del_19p 0.61447685 — — — wa_del_19p amp_19q13.2 0.61443667 — — amp_19q13.2 — amp_12p11.22 0.60473038 — — amp_12p11.22 — amp_6q23.3 0.6007847 — — — amp_6q23.3 wa_del_1q 0.5932403 — — wa_del_1q — del_8q11.1 0.59224336 — del_8q11.1 — — wa_del_19q 0.58885616 — — wa_del_19q — wa_del_12p 0.58033903 — — — wa_del_12p wa_amp_5p 0.58007436 — — wa_amp_5p — del_6p25.3 0.57614983 del_6p25.3 — — — amp_17q25.3 0.57546275 — — amp_17q25.3 — amp_2q33.1 0.57035447 — — amp_2q33.1 — wa_amp_12p 0.56509266 — — — wa_amp_12p wa_del_6q 0.55451621 — wa_del_6q — — wa_del_9q 0.54581935 — — wa_del_9q — amp_3q29 0.54264532 — amp_3q29 — — amp_11p15.5 0.54017534 — — amp_11p15.5 — amp_17q24.2 0.53976335 — amp_17q24.2 — — del_12q24.33 0.53826885 — — del_12q24.33 — wa_amp_2q 0.53771069 — — — wa_amp_2q wa_amp_6q 0.53538285 — — — wa_amp_6q del_5p15.33 0.52968199 — — del_5p15.33 — wa_del_3p 0.52919712 — — wa_del_3p — amp_17q23.2 0.52759456 — amp_17q23.2 — — wa_amp_9p 0.52569831 — — — wa_amp_9p del_2p25.3 0.52195842 — — — del_2p25.3 wa_del_6p 0.51638946 — wa_del_6p — — amp_19q13.11 0.51402152 — — amp_19q13.11 — del_6p22.2 0.51056665 del_6p22.2 — — — wa_amp_2p 0.50462529 — — — wa_amp_2p wa_amp_3q 0.48576757 — — wa_amp_3q — wa_amp_19q 0.48190073 — — — wa_amp_19q del_3q26.31 0.47316393 — — del_3q26.31 — wa_amp_12q 0.4694395 — — — wa_amp_12q wa_del_20p 0.46181551 — — wa_del_20p — amp_11q13.3 0.45349829 — — amp_11q13.3 — del_16q23.1 0.45142138 — — del_16q23.1 — del_16p13.3 0.45028421 — — del_16p13.3 — wa_amp_9q 0.43896029 — wa_amp_9q — — wa_amp_10p 0.43821908 — — — wa_amp_10p amp_15q26.1 0.43390108 — — — amp_15q26.1 wa_amp_19p 0.42292166 — — wa_amp_19p — wa_amp_11p 0.42185291 — — wa_amp_11p — wa_amp_21q 0.38128102 — — — wa_amp_21q wa_amp_17p 0.3799839 — — — wa_amp_17p wa_del_3q 0.37733862 — — wa_del_3q — wa_amp_3p 0.3694481 — — — wa_amp_3p wa_amp_11q 0.36247292 — — wa_amp_11q — wa_del_16p 0.36136172 — — — wa_del_16p del_2q37.3 0.34823854 — — — del_2q37.3 wa_amp_1p 0.34348283 — — wa_amp_1p — wa_del_16q 0.32026275 — — — wa_del_16q del_2p21 0.31250652 — — del_2p21 — del_2q23.1 0.29511207 — — — del_2q23.1 wa_amp_5q 0.2792709 — — — a_amp_5q amp_10q22.3 0.27562286 — — — amp_10q22.3 amp_18q11.2 0.2636361 — — — amp_18q11.2 wa_amp_14q 0.25989981 — — — wa_amp_14q amp_1p34.2 0.25159063 — — — amp_1p34.2 wa_del_8q 0.24836297 — — wa_del_8q — wa_amp_10q 0.21366949 — — — wa_amp_10q wa_amp_18p 0.20445617 — — — wa_amp_18p wa_amp_4p 0.18414829 — — — wa_amp_4p del_7q31.1 0.15773653 — — — del_7q31.1 wa_amp_18q 0.14698558 — — — wa_amp_18q amp_18q21.1 0.145565 — — — amp_18q21.1 wa_del_7q 0.13516126 — — — wa_del_7q wa_del_13q 0.13461326 — — — wa_del_13q wa_del_2p 0.11809222 — — — wa_del_2p wa_del_2q 0.11400227 — — — wa_del_2q wa_amp_15q 0.10837076 — — — wa_amp_15q wa_amp_22q 0.09878651 — — — wa_amp_22q wa_amp_4q 0.09805239 — — wa_amp_4q — wa_del_7p 0.04804664 — — — wa_del_7p wa_del_20q 0 — — — wa_del_20q

TABLE 16 Comparison between recursive partitioning tiers and the contribution to the random forest model for each of the 102 focal genomic regions. Genomic regions are listed by their descriptor name. Full information of these markers (e.g. peak limits and region limits) can be retrieved from Table 5 using the descriptor name. Descriptor name Contribution Tier 1 Tier 2 Tier 3 del_4q25 9.194419 — del_4q25 — del_4q32.1 8.1782609 del_4q32.1 — — del_4q31.3 8.0446448 del_4q31.3 — — del_4q22.1 7.8661453 del_4q22.1 — — del_4q35.1 7.1401903 — del_4q35.1 — amp_20q13.12 4.6635259 amp_20q13.12 — — amp_20q11.21 4.4202524 — amp_20q11.21 — del_4p16.2 4.4096883 — del_4p16.2 — amp_20q13.2 4.2672955 amp_20q13.2 — — del_22q13.32 4.1267928 del_22q13.32 — — del_21q11.2 4.0776699 del_21q11.2 — — del_21q21.1 3.9182542 del_21q21.1 — — amp_20q13.32 3.5799093 amp_20q13.32 — — del_15q22.33 3.455251 del_15q22.33 — — del_10q23.31 3.369556 del_10q23.31 — — del_10q21.1 3.1436983 del_10q21.1 — — del_18q21.2 2.905616 del_18q21.2 — — del_10q25.2 2.7938966 del_10q25.2 — — del_1p31.1 2.7530879 — del_1p31.1 — del_1p21.1 2.6974638 — del_1p21.1 — del_18q12.2 2.6594014 del_18q12.2 — — del_18q21.33 2.5200778 — del_18q21.33 — amp_20p12.1 2.5116485 amp_20p12.1 — — del_11q22.3 2.4935124 del_11q22.3 — — del_1p33 2.4544835 — del_1p33 — del_15q11.2 2.3805641 — del_15q11.2 — del_10q26.3 2.3715158 — del_10q26.3 — del_18p11.31 2.3395225 — del_18p11.31 — amp_20p11.22 2.3155324 amp_20p11.22 — — del_17p12 2.2734537 — del_17p12 — del_15q21.1 2.2056725 — del_15q21.1 — del_5q22.2 2.1163858 del_5q22.2 — — amp_20p12.3 2.064109 amp_20p12.3 — — del_8p23.3 2.0464708 del_8p23.3 — — amp_13q12.2 2.0138841 — amp_13q12.2 — del_5q12.1 1.9727809 — del_5q12.1 — amp_13q22.1 1.9642941 — amp_13q22.1 — amp_8q21.13 1.7754935 amp_8q21.13 — — del_10p15.3 1.7489137 — del_10p15.3 — del_14q24.1 1.7375301 — del_14q24.1 — del_12q21.2 1.7138062 del_12q21.2 — — del_14q32.11 1.7100382 del_14q32.11 — — amp_8q22.3 1.6977776 amp_8q22.3 — — del_1p36.11 1.655325 — — del_1p36.11 del_1p36.31 1.6275767 — — del_1p36.31 amp_13q34 1.6177405 — amp_13q34 — del_20p12.1 1.5555618 — del_20p12.1 — amp_8q12.2 1.5323055 — amp_8q12.2 — del_8p21.3 1.5316374 — del_8p21.3 — del_19p13.3 1.5195977 — del_19p13.3 — del_8p12 1.5162631 — del_8p12 — amp_8p11.21 1.5015065 amp_8p11.21 — — amp_5p12 1.4519356 — amp_5p12 — amp_8q24.21 1.4373339 — amp_8q24.21 — del_3p13 1.4356909 del_3p13 — — del_3p26.3 1.4256335 — del_3p26.3 — amp_7p11.2 1.3851619 — amp_7p11.2 — amp_1q43 1.3355112 — amp_1q43 — del_6q26 1.3326207 del_6q26 — — del_6q21 1.3147804 del_6q21 — — del_17q24.3 1.2848234 — del_17q24.3 — amp_6p21.1 1.2774639 — amp_6p21.1 — amp_5p15.33 1.2446252 — — amp_5p15.33 amp_8p11.23 1.2319335 — amp_8p11.23 — del_9p21.3 1.1988554 — — del_9p21.3 amp_16p11.2 1.197811 — amp_16p11.2 — del_3p14.2 1.1379309 — — del_3p14.2 amp_1q22 1.1037294 amp_1q22 — — del_12q24.33 1.092504 — — del_12q24.33 amp_17q11.2 1.0736711 amp_17q11.2 — — amp_17q12 1.061722 — amp_17q12 — del_5p15.33 1.0603831 — — del_5p15.33 amp_16q12.1 1.0570224 — — amp_16q12.1 amp_12p11.22 1.0564938 — — amp_12p11.22 amp_2q33.1 1.0392578 — amp_2q33.1 — amp_17q25.3 1.0214531 — — amp_17q25.3 del_12p13.2 1.01047 — del_12p13.2 — amp_3q29 1.0074218 — — amp_3q29 amp_6q23.3 0.9983965 — amp_6q23.3 — del_6p22.2 0.9867404 del_6p22.2 — — amp_17q24.2 0.9853368 — amp_17q24.2 — amp_17q23.2 0.928049 — — amp_17q23.2 del_8q11.1 0.9098856 — — del_8q11.1 amp_11p15.5 0.9026687 — amp_11p15.5 — del_6p25.3 0.8969569 del_6p25.3 — — amp_12p13.32 0.892304 — — amp_12p13.32 amp_19q13.2 0.8844445 — — amp_19q13.2 del_16q23.1 0.8843983 — del_16q23.1 — amp_19q13.11 0.880044 — — amp_19q13.11 del_2p25.3 0.7876138 — — del_2p25.3 del_3q26.31 0.7648052 — del_3q26.31 — del_16p13.3 0.6998853 — — del_16p13.3 amp_11q13.3 0.6309478 — — amp_11q13.3 amp_15q26.1 0.5231053 — amp_15q26.1 — del_2q37.3 0.5216232 — — del_2q37.3 del_2q23.1 0.5056672 — — del_2q23.1 amp_18q11.2 0.4808792 — — amp_18q11.2 del_2p21 0.4489627 — — del_2p21 amp_1p34.2 0.4346417 — — amp_1p34.2 amp_10q22.3 0.3836683 — — amp_10q22.3 amp_18q21.1 0.2879049 — — amp_18q21.1 del_7q31.1 0.2331979 — — del_7q31.1

TABLE 17 Report on random forest classifier and k-nearest neighbor classifiers Statistics by class Cluster 1 Cluster 2 Cluster 3 Random forest - Using all 180 regions Accuracy: 0.9412 95% CI: (0.915, 0.9612) Sensitivity 1 0.881 0.9744 Specificity 0.99751 0.9781 0.9087 Balanced Accuracy 0.99876 0.9295 0.9415 Random forest - Using the 102 focal regions Accuracy: 0.9389 95% CI: (0.9124, 0.9594) Sensitivity 1 0.8929 0.9615 Specificity 1 0.9672 0.9135 Balanced Accuracy 1 0.93 0.9375 k-nearest neighbor - Using all 180 regions Accuracy: 0.8643 95% CI: (0.8287, 0.8948) Sensitivity 1 0.9167 0.8034 Specificity 0.9577 0.8577 0.9808 Balanced Accuracy 0.9789 0.8872 0.8921 k-nearest neighbor - Using the 102 focal regions Accuracy: 0.8733 95% CI: (0.8386, 0.9029) Sensitivity 1 0.9226 0.8162 Specificity 0.9677 0.8613 0.976 Balanced Accuracy 0.9838 0.892 0.8961

TABLE 18 The relation of copy number instability in different subsets of regions and the response to Avastin. P stands for predictive for copy number instability, NP stands for not predictive for copy number instability. The relative number of regions affected by CNAs can be seen as a measure for copy number instability. Using different thresholds to define tumors as copy number unstable and stratify the patients accordingly we were able to observe beneficial responses to Avastin treatment for tumor instabilities ranging from 10% to 40% of regions affected by CNAs. We performed this analysis on 6 different subsets (1) using only the 102 focal regions, (2) using the top 50 ranked regions from the random forest classification model built with the 102 focal regions, (3) using the tier 1 and tier 2 regions from the recursive partitioning applied on the 102 focal regions, (4) using all 180 genomic regions (5) using the tier 1 and tier 2 regions from the recursive partitioning applied all 180 regions and (6) using the top 50 ranked regions from the random forest classification model built with the 180 focal regions. % of regions affected 1th quartile 1th quartile 10% 15% 20% 25% 30% 35% 40% (1) Regions from Table 5 27% P P P P P P P NP (2) Top 50 ranked regions from Table 14 38% P P P P P P P P (3) Regions from Table 10 and 11 33% P P P P P P P P (4) Regions from Table 1 22% P P P P P NP NP NP (6) Top 50 ranked regions from Table 15 36% P P P P P P P P (5) Regions from Table 6 and 7 31% P P P P P P P P

Materials and Methods

Sample Collection

Tumor tissue of 278 CRC patients receiving combination bevacizumab treatment or chemotherapeutic agents alone were identified and provided from the tissue bio-banks of the Royal College of Surgeons in Ireland (RCSI) Beaumont Hospital (n=29), The University of Heidelberg (UHEI) in Germany (n=107) and the VU university medical centre (VUMC) in The Netherlands (n=142). A second cohort 106 of combination bevacizumab treated tumors and accompanying normal tissue from the MOMA clinical trial was provided by The University of Pisa in Italy (NCT02271464). Informed consent was obtained from the patient, following the ethical approval of the local ethical committee. After tissue collection, samples were reviewed by qualified pathologists to reconfirm cancer diagnosis and delineate adjacent normal tissue. Only tumor blocks with (1) at least 30% tumor cell content, as judged by a routine hematoxylin and eosin (H&E) staining, (2) sufficient tissue volume in order to allow successful DNA isolation and (3) clinical data available were considered for further processing and analysis. Additionally we downloaded publicly available copy number data of a cohort of 205 patients from the CAIRO trial that were treated with Irinotecon-Capecitabine (CAPIRI) or capecitabine (CAP) only (Agilent oligonucleotide hybridization arrays; GSE36864) (Haan et al 2014).

DNA Isolation

After pathological examination, 1-10 FFPE slides (5-10 μm) were used for DNA extraction. Regions with high tumor content as well as regions containing only normal cells as indicated by the pathologist were macro-dissected from individual slides. Subsequently the FFPE tissue sections are deparaffinised using a series of xylene and ethanol washes. The sections were then subjected to purification and homogenization (by gentle shaking at 400 rpm while incubation in buffer ALT and Proteinase K at 56° C.) to remove fixatives and aid lysis. After deparaffinisation and tissue digestion, DNA was further extracted using the QIAamp DNA FFPE Tissue kit (QIAgen) following the manufacturer's instructions. The resulting DNA was quantified using the Picogreen Assay (Life Technologies) following the manufacturer's instructions. This assay allows to accurately determine the concentration of double-strand DNA needed for further sequencing library preparation. Only samples with a yield of more than 0.5 μg of dsDNA and a concentration >7.5 ng/μl were selected for further library preparation.

Low-Coverage Whole Genome Sequencing

Shot-gun whole genome libraries were prepared using KAPA library preparation kit (KAPA Biosystems). Since the DNA was extracted from FFPE tissue blocks, whole genome DNA libraries from matched normal and tumor tissue samples were created according to the manufacturer's instructions with some modifications to the protocol. Before end repair, a 4 hour incubation step at 65° C. was added to remove as many reversible crosslinks as possible after which excessive single stranded DNA was removed using Mung-Bean nuclease. The concentration double stranded DNA was reassessed using picogreen and the concentration of adapters used in the ligation step of the library construction was altered according to the present DNA. For the library enrichment, 5 to 15 cycles of PCR with intermediate assessment steps were used instead to ensure low adapter dimer content and high library yield. After quantification with qPCR, the resulting libraries were sequenced on a HiSeq2500 (Illumina) at low coverage (±0.1×). Raw sequencing reads were mapped to the human reference genome (NCBI37/hg19) using Burrows-Wheeler Aligner (BWA v0.5.8a) (Li and Durbin 2010). Picard (v1.43) was used to remove PCR duplicates. CNAs were identified by binning the reads in 30 Kb windows, correcting for genomic waves using the PennCNV software package (Wang et al 2007) and the resulting number of reads per 30 Kb window were transformed into log R-values. The ASCAT algorithm version 2.0.1 (Van Loo et al 2010) was used to segment the raw data and estimate tumor percentages and overall ploidy. Subsequently, GISTIC v2.0 (Mermel et al 2011) was used to identify the most frequent and overrepresented chromosomal aberrations in tumors. A region was considered deleted if the log R value was <0.1 and amplified when the log R was >0.1 A cut-off q-value of 0.25 was used to select significantly overrepresented CNAs. CNAs spanning >70% of a chromosomal arm were defined as whole-arm CNAs, while CNAs spanning <70% of a chromosomal arm were considered focal CNAs. Significant amplified or deleted regions were assigned as homozygous deletion, loss, diploid, gain or amplification for each sample based on Log R signal and GISTIC output threshold values (t<−1.3; −1.3<t<−0.1; −0.1<t<0.1; 0.1<t<0.9; t>0.9 respectively).

Whole-Exome Sequencing

After confirmation of successful library construction, whole exome enrichment was performed using the SeqCapV3 exome enrichment kit (Roche) following the manufacturer's instructions. The resulting whole-exome libraries were then sequenced on a HiSeq2500 using a V3 flowcell generating 2×100 bp paired end reads. Raw sequencing reads were mapped to the human reference genome (NCBI37/hg19) using Burrows-Wheeler Aligner (BWA v0.5.8a) (Li and Durbin 2010) and aligned reads were processed and sorted with SAMtools (v0.1.19) (Li et al 2009). Duplicate reads were removed using Picard tools. Base recalibration, local realignment around insertions and deletions and single nucleotide variant calling were performed using the GenomeAnalysisToolKit (GATK) (McKenna et al 2010). Insertions and deletions were called using Dindel (Albers et al 2011). By subtracting variants and indels detected in the matched germline DNA from those found in the tumor DNA, somatic mutations were selected. Low quality mutations were removed based on mapping quality and coverage. ANNOVAR (Wang et al 2010) was used to annotate the remaining mutations and exonic non-synonymous mutations and frame-shift insertions or deletions were selected. Common variants (MAF>1%) were filtered out using the following databases as described previously (Zhao et al 2014): (1) dbSNP version 132, (2) 1000 Genomes Project, (3) Axiom Genotype Data Set, (4) Complete Genomics diversity panel (46 hapmap individuals).

Statistical Analysis

Consensus clustering using unsupervised Hierarchical Ward clustering was performed using the packages ‘ConsensusClusterPlus’ and ‘hclust’ in R on all samples using the recurrent CNAs identified from the GISTIC analysis on all mCRC samples as input using a subsampling size of 80% and 50 repetitions. Multivariate survival analysis between the different clusters was performed using a Cox regression analysis using TNM staging and age as numerical factors while gender and the cluster were used as categorical factors. For each cluster and to compare CNA-high with CNA-low patients, survival of patients receiving combination bevacizumab therapy was compared with patients treated with chemotherapy in a univariate analysis using the Kaplan Meier method and evaluated with a log rank-test. Recursive partitioning was performed using the R-package ‘rpart’ using the ‘class’ method. To determine the different tiers we used all 180 regions to build a first most optimal regression tree. Next, in a stepwise manner we removed one of the regions used in the tree and generated a second tree, after that we reinserted that specific region again and removed another region and generated a third, fourth, fifth etc. . . . tree. By performing this on 4 different levels (each time removing and replacing one of the used regions) we selected the most important regions based on recurrent selection by the recursive partitioning. The CNAs selected after the first analysis completed 4 levels were assigned to tier 1, removed from the list of 180 regions and the process was repeated to generate tier 2, tier 3 and tier 4. A similar approach was used for the 102 focal regions to determine tier 1, tier 2 and tier 3 regions. Random forest classification was performed using the R-package ‘rf’ using. K-nearest neighbors classification was performed using the package ‘knn’. For both the random forest and k-nearest neighbors classifiers, we performed a 10-fold cross-validation on the original dataset to determine the accuracy of the model. Hereto, we divided the 442 mCRC samples used for the original clustering 10 times at random, each time in a training set (90% of the samples) and validation set (10% of the samples) in such a manner that each sample is presented only once in the whole of 10 validation sets. Next a random forest classifier was generated using the training data. We then applied this classifier to the validation data to determine the models accuracy.

REFERENCES

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1. A colorectal cancer biomarker panel comprising at least 5 genomic DNA regions or fragments thereof selected from Table
 1. 2. A method of measuring the copy number alteration status of a colorectal cancer sample, the method comprising: obtaining the colorectal cancer sample; and measuring, in the colorectal cancer sample, the copy number alteration status of the genomic regions of the colorectal biomarker panel of claim
 1. 3. A method of measuring the copy number instability of a colorectal cancer sample the method comprising: obtaining the colorectal cancer sample; and measuring the copy number instability of the genomic regions in the colorectal biomarker of claim
 1. 4.-9. (canceled)
 10. A method for the treatment of a subject suffering from colorectal cancer with anti-VEGF therapy, the method comprising: measuring, in the colorectal cancer sample, the copy number alteration status of the genomic regions of the colorectal biomarker panel of claim 1 classifying the colorectal cancer sample as being one of genetic subtypes 2 or 3 as depicted in Table 3 or 4; and treating the subject with anti-VEGF therapy.
 11. A method for the treatment of a subject suffering from colorectal cancer with anti-VEGF therapy, the method comprising: measuring a copy number instability of 15% or more in a colorectal cancer sample from the subject utilizing the biomarker panel of claim 1, and treating the subject with anti-VEGF therapy. 